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Aktivitas antimikroba dari flavonoid.


Artikel ​dalam J​ urnal Internasional Agen Antimikroba · Desember 2005
DOI: 10.1016 / j.ijantimicag.2005.09. 002 · Sumber: PubMed
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Tim Cushnie ​Mahasarakham Universitas
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MELIHAT PROFIL
Andrew J Lamb ​Robert Gordon University
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Kedokteran HewanFarmasi ​ProyekLihat
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Cushnie TPT, Lamb AJ. Aktivitas antimikroba dari flavonoid. Jurnal Internasional
Agen Antimikroba, 2005. 26 (5): 343-356. PMID: 16323269 DOI: 10.1016 /
j.ijantimicag.2005.09.002

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Tinjau ​aktivitas antimikroba flavonoid
TP Tim Cushnie, Andrew J. Lamb​∗
Sekolah Farmasi, Universitas Robert Gordon, Schoolhill, Aberdeen AB10 1FR, UK

Abstrak

Flavonoid ada di mana-mana dalam sel fotosintesis dan umumnya ditemukan dalam buah, sayuran, kacang-kacangan, biji-bijian,
batang, bunga, teh, anggur, propolis, dan madu. Selama berabad-abad, preparat yang mengandung senyawa-senyawa ini sebagai
unsur utama aktif fisiologis telah digunakan untuk mengobati penyakit manusia. Semakin lama, kelas produk alami ini menjadi
subjek penelitian anti-infeksi, dan banyak kelompok telah mengisolasi dan mengidentifikasi struktur flavonoid yang memiliki
aktivitas antijamur, antivirus, dan antibakteri. Selain itu, beberapa kelompok telah menunjukkan sinergi antara flavonoid aktif
serta antara flavonoid dan kemoterapi yang ada. Laporan aktivitas di bidang penelitian flavonoid antibakteri sangat bertentangan,
mungkin karena variasi antar dan intra-tes dalam pengujian kerentanan. Namun, beberapa investigasi berkualitas tinggi telah
meneliti hubungan antara struktur flavonoid dan aktivitas antibakteri dan semua ini dalam persetujuan. Selain itu, banyak
kelompok penelitian telah berusaha menjelaskan mekanisme aksi antibakteri flavonoid terpilih. Aktivitas quercetin, misalnya,
setidaknya sebagian dikaitkan dengan penghambatan DNA girase. Juga telah diusulkan bahwa sophoraflavone G dan (​-​)
-pigallocatechin gallate menghambat fungsi membran sitoplasma, dan bahwa licochalcone A dan C menghambat metabolisme
energi. Flavonoid lain yang mekanisme kerjanya telah diselidiki termasuk robinetin, myricetin, apigenin, rutin, galangin, 2,4,2
-trihydroxy-5-methylchalcone dan lonchocarpol A. Senyawa ini mewakili arahan baru, dan studi di masa depan memungkinkan
pengembangan suatu agen antimikroba yang dapat diterima secara farmakologis atau kelas agen. © 2005 Elsevier BV dan
Masyarakat Kemoterapi Internasional. Seluruh hak cipta.

Kata kunci: ​Flavonoid; Antijamur; Antiviral; Antibakteri; Struktur – aktivitas; Mekanisme tindakan

262 555.
Alamat email: a​ .lamb@rgu.ac.uk (AJ Lamb).
termasuk ​ß​-laktam dan kuinolon ​[5]​. Maka tidak
1. Pendahuluan mengherankan, bahwa dalam menanggapi resistensi
antimikroba, perusahaan farmasi besar cenderung
Resistansi terhadap agen antimikroba telah menjadi memusatkan upaya mereka pada peningkatan agen
masalah global yang semakin penting dan mendesak. antimikroba di kelas yang sudah mapan ​[6]​. Namun,
Dari 2 juta orang yang mendapatkan infeksi bakteri dengan portofolio kemoterapi yang tersedia saat ini,
di rumah sakit AS setiap tahun, 70% kasus sekarang telah diakui bahwa para peneliti semakin mendekati
melibatkan jenis yang resisten terhadap setidaknya akhir permainan dalam hal perubahan struktur induk.
satu obat ​[1]​. Penyebab utama yang perlu Oleh karena itu panggilan telah dibuat untuk
dikhawatirkan di Inggris adalahresistan terhadap pengembangan kelas obat baru yang bekerja di situs
metisilin ​Staphylococcus aureus (​ MRSA) yang, yang target yang berbeda dengan yang digunakan saat ini
berada pada level rendah satu dekade lalu, tetapi [7,8]​.
sekarang menjadi sekitar ca. 50% dari semua​S. Rancangan obat rasional tidak selalu menghasilkan
aureus ​isolat ​[2]​. Investasi besar dan penelitian di antimikroba yang efektif. Di masa lalu, inhibitor
bidang anti-infeksi sekarang sangat dibutuhkan jika enzim ampuh telah berhasil dirancang dan disintesis
krisis kesehatan masyarakat harus dihindari. tetapi mereka hanya memiliki aktivitas antibakteri
Modifikasi struktural obat antimikroba yang telah sederhana, mungkin karena masalah rumit dari
dikembangkan resistensi telah terbukti menjadi cara penyerapan obat oleh sel. Skrining empiris yang luas
yang efektif untuk memperpanjang umur agen dari entitas kimia untuk aktivitas antimikroba
antijamur seperti azole ​[3]​, agen antivirus seperti merupakan strategi alternatif untuk pengembangan
inhibitor transkriptase nukleosida terbalik ​[4]​, dan obat baru. Produk alami telah menjadi sumber yang
berbagai antibakteri agen kaya agen anti infeksi, menghasilkan, misalnya,
penisilin pada tahun 1940, tetrasiklin pada tahun
1948 dan glikopeptida pada
∗​
Penulis yang sesuai. Tel .: +44 1224 262 526; faks: +44 1224

0924-8579 / $ - lihat materi depan © 2005 Elsevier BV dan International Society of Kemoterapi. Seluruh hak cipta. doi: 10.1016 /
j.ijantimicag.2005.09.002
Jurnal Internasional Agen Antimikroba 26 (2005) 343-356
344 ​TPT Cushnie, AJ Lamb / Jurnal Internasional Agen Antimikroba 26 (2005) 343-356
sediaan herbal yang mengandung flavonoid ​[14]​.
1955 ​[9]​. Ulasan berikut ini akan memeriksa Fungsi flavonoid pada bunga adalah memberikan
aktivitas antimikroba dari flavonoid, kelas produk warna yang menarik bagi penyerbuk tanaman
alami yang memiliki beragam sifat farmakologis. [11,15]​. Dalam daun, senyawa ini semakin dipercaya
Senyawa dengan aktivitas antijamur, antivirus dan untuk meningkatkan kelangsungan hidup fisiologis
antibakteri masing-masing akan dibahas secara tanaman, melindunginya dari, misalnya, patogen
berurutan, dengan penekanan khusus pada flavonoid jamur dan radiasi UV-B ​[13,15]​. Selain itu, flavonoid
dengan aktivitas antibakteri. terlibat dalam fotosensitisasi, transfer energi, aksi
hormon pertumbuhan tanaman dan pengatur
pertumbuhan, kontrol respirasi dan fotosintesis,
2. Flavonoid: kejadian, fungsi, struktur dan morfogenesis, dan penentuan jenis kelamin ​[11,13]​.
nomenklatur Fitur struktural dasar senyawa flavonoid adalah
2-phenyl-benzo [​α​] pyrane atau nukleus flavana,
Flavonoid ada di mana-mana dalam sel fotosintesis yang terdiri dari dua cincin benzena (A dan B) yang
dan karena itu terjadi secara luas di kerajaan tanaman dihubungkan melalui cincin pyrane heterosiklik (C)
[10]​. Mereka ditemukan dalam buah, sayuran, (​Gbr. 1​) ​[16]​. Flavonoid dapat diklasifikasikan
kacang-kacangan, biji-bijian, batang dan bunga serta menurut asal biosintesis. Beberapa kelas, misalnya
teh, anggur ​[11]​, propolis dan madu ​[12]​, dan chalcone, flavanones, flavan-3-ols dan
mewakili konstituen umum dari makanan manusia flavan-3,4-diol, keduanya merupakan perantara
[13]​. Di AS, asupan harian flavonoid campuran dalam biosintesis serta produk akhir yang dapat
diperkirakan berkisar 500-1000 mg, tetapi angka ini terakumulasi dalam jaringan tanaman. Kelas-kelas
bisa setinggi beberapa gram untuk orang yang lain hanya dikenal sebagai produk akhir dari
melengkapi diet mereka dengan flavonoid atau biosintesis, misalnya antosianidin, proantosianidin,
flavon dan flavonol. Dua golongan flavonoid
tambahan adalah di mana rantai sisi 2-fenil dari
flavanon mengisolasi ke posisi 3, sehingga 3. Sifat obat flavonoid
menimbulkan isoflavon dan isoflavonoid
terkait.tersebut. Semakin, flavonoid menjadi subjek penelitian medis.
Mereka telah dilaporkan memiliki banyak sifat yang
berguna, termasuk aktivitas antiinflamasi, aktivitas
estrogen, penghambatan enzim, aktivitas antimikroba
[10,13]​, aktivitas anti alergi, aktivitas antioksidan
[11]​, aktivitas vaskular dan aktivitas antitumor
sitotoksik ​[15]​. Untuk sekelompok senyawa dengan
struktur yang relatif homogen, flavonoid
menghambat jumlah dan variasi enzim eukariogen
yang membingungkan dan memiliki aktivitas yang
sangat beragam. Dalam hal penghambatan enzim, ini
telah dipostulatkan karena interaksi enzim dengan
Gambar 1. Struktur rangka dari flavon (kelas flavonoid), dengan bagian-bagian berbeda dari molekul flavonoid,
cincin nama dan posisi bernomor [13]. misalnya karbohidrat, cincin fenil, cincin fenol dan
neoflavonoid dibentuk melalui isomerisasi lebih cincin benzopron ​[10]​. Beberapa ulasan telah ditulis
lanjut ke posisi 4 ​[13]​. Struktur kelas utama tentang interaksi antara flavonoid dan sel mamalia,
flavonoid diberikan pada ​Gambar. 2​. Struktur termasuk artikel komprehensif oleh Harborne dan
senyawa spesifik dalam kelas-kelas ini yang Williams ​[15] ​dan Middleton et al. ​[20].​Tinjauan luas
memiliki aktivitas antimikroba dan yang dibahas tentang biokimia dan signifikansi medis flavonoid
dalam ulasan ini dirangkum dalam ​Tabel 1​. juga baru-baru ini diproduksi oleh Havsteen ​[21]​.
Flavonoid individu dapat diberi nama dengan tiga
cara berbeda. Nama-nama sepele digunakan secara
luas dan kadang-kadang menunjukkan kelas 4. Sejarah penggunaan flavonoid dalam
flavonoid atau sumber tanaman. Sebagai contoh, pengobatan antimikroba
nama-nama yang berakhiran 'inidin' dapat
menunjukkan suatu antosianidin, nama-nama yang Selama berabad-abad, persiapan yang mengandung
berakhiran 'etin' umumnya menunjukkan suatu flavonoid sebagai konstituen aktif fisiologis utama
flavonol, dan senyawa-senyawa tricin dan hypolaetin telah digunakan oleh dokter dan penyembuh awam
telah diekstraksi dari tanaman-tanaman milik genera dalam upaya untuk mengobati penyakit manusia
Triticum ​dan ​Hypolaena​. Flavonoid juga dapat [10]​. Sebagai contoh, tanaman​Tagetes
dinamai dengan cara semi-sistematis berdasarkan minuta​(mengandung
pada nama-nama sepele seperti flavon atau chalcone quercetagetin-7-arabinosyl-galactoside) telah
sebagai struktur induk, misalnya 3,5,7,3 digunakan secara luas dalam pengobatan tradisional
4-pentahydroxyflavone atau 3,3, 4, Argentina untuk mengobati penyakit menular ​[22]​.
5,7-pentahydroxyflavone . Terakhir, flavonoid dapat Sifat penyembuhan propolis (atau 'tzori' dalam
diberi nama kimia yang sistematis, misalnya bahasa Ibrani) disebut di seluruh Perjanjian Lama
3,4-dihydro-2-phenyl-2H-1-benzopyran untuk [23]​, dan balsem ini diresepkan oleh Hippocrates
flavan, tetapi metode ini rumit dan jarang digunakan (460-377 SM) di Yunani Kuno untuk pengobatan
[13]​. Dalam ulasan ini, nama-nama sepele akan luka dan bisul ​[24]​.
digunakan sedapat mungkin.
flavanon-3-ols ​[13]​, anthocyanidins ​[13,20]​, flavan-3-ols ​[10,13]​, proanthocyanidins (muncul dalam bentuk dimer, trimers, tetramers dan
pentamers; ​R ​= 0, 1, 2 atau 3 flavan- 3-ol struktur) ​[13]​, flavans ​[13]​, flavan-3,4-diol ​[13] ​dan dihydrochalcones ​[13]​.
TPT Cushnie, AJ Lamb / Jurnal Internasional Agen Antimikroba 26 (2005) 343-356 3​ 45
346 ​TPT Cushnie, AJ Lamb / Jurnal Internasional Agen Antimikroba 26 (2005) 343-356
Tabel 1 Ringkasan struktur flavonoid antimikroba yang dibahas dalam artikel ulasan ini (disusun dari The Handbook of Natural Flavonoids ​[13]
dan masing-masing makalah penelitian)
Senyawa Substituen pada posisi karbon:
234567823456
Flavon dan glikosida mereka

Acacetin - - - OH - OH - - - OCH​3 ​- - Apigenin


​ - - - OH - OH - - - OH - - Baicalin - - - OH OH OR1 - - - - - - Baicalein - - - OH OH OH - - - - - - -

Chrysin - - - OH - OH - - - - - - Gardenin A (demethylated) - - - OH OH OH OH - OH OH OH - Genkwanin - - - OH - OCH​3 ​- - - OH - - ​Luteolin -


- - OH - OH - - OH OH - - Luteolin 7-glukosida - - - OH - OR2 - - OH OH - - 7,8- Dihydroxyflavone - - - - - OH OH - - - - - 5,5 -Dihydroxy-8,2, 4

-rimrimoxyflavone - - - OH - - OCH​3 ​OCH​3 ​- OCH​3 ​OH - 5-Hydroxy-7,4 -dimethoxyflavone - - - OH - OCH​3 ​- - - OCH​3 ​- - 5,7,4
​ -Trihydroxy-3, 5

-dimethoxyflavone - - - OH - OH - - CH​3 ​OH CH​3 ​- 6,7,4


​ -Trihydroxy-3 , 5 -dimethoxyflavone - - - - OH OH - - CH​3 OH
​ CH​3 -​
Isoflavon
6,8-Diprenylgenistein - - - OH R3 OH R3 - - OH - - Sophoraisoflavone A - - - OH - OH - * * OH - -
Flavonol dan glikosida mereka

​ etilquercetin - OCH​3 ​- OH - OH - - OH OH - - Morin


Galangin - OH - OH - OH - - - - - Kaempherol - OH - OH - OH - - - OH - - 3-​O-m ​ - OH - - -
OH - OH - OH OH - Myricetin - OH - OH - OH - - OH OH OH - Quercetagetin - OH - OH OH OH - - OH OH - -
Quercetagetin-7-arabinosyl-galactoside - OH - OH OH OR4 - - OH OH - - Quercetin - OH - OH - OH - - OH OH - - Quercetin-3-​O-​ (2 -allalll)
-​α​-​L​- arabinopyranoside
- OR5 - OH - OH - - OH OH - -
Quercetrin - OR6 - OH - OH - - OH OH - - Robinetin - OH - - - OH - - OH OH OH - Rutin - OR7 - OH - OH - - OH OH - - 3,2
-Dihydroxyflavone - OH - - - - - OH - - - - 3, 6,7,3, 4-Pentahydroxyflavone - OH - - OH OH - - OH OH - -
Flavan-3-ols
Catechin - OH OH - - OH - - OH - OH - OH - OH - Epicatechin gallate - R8 - OH - OH - - OH OH - - Epigallocatechin - OH - OH - OH - - OH
OH OH - Epigallocatechin gallate - R8 - OH - OH - - OH OH OH - 3-​O​-octanoyl - (+) - catechin - R9 - OH - OH - - OH OH - - 3-​O-​ octanoyl- (​-​)
-epicatechin - R9 - OH - OH - - OH OH - -
Flavanon-3-ols
Dihydrofisetin - OH - - - OH - - OH OH - - Dihydroquercetinetin - OH - OH - OH - - OH OH - -
Flavanon es dan glikosida mereka
Lonchocarpol A - - - OH R3 OH R3 - - OH - - Naringenin - - - OH - OH - - OH - - Naringin - - - OH - OR7 - - - OH - - Pinocembrin - - - OH - OH

- - - - - - Ponciretin - - - OH - OH - - - OCH​3 ​- - Sophoraflavanone


​ G - - - OH - OH R10 OH - OH - - 3-Methyleneflavanone - CH​2 -​ - - - - - - - - - -
5,7,4 -Trihydroxy-8-methyl-6- (3-methyl- [2- butenyl]) - (2​S)​ -flavanon

- - - OH R3 OH CH​3 ​- - OH - -
Chalcones

Licochalcone A - R11 OH - OCH​3 ​- - - - OH - - Licochalcone


​ C - - OH R3 OCH​3 ​- - - - OH - - 2,4,2
​ -Trihydroxychalcone OH - OH - - - - OH - - -

- 2,4, 2 -Trihydroxy-5 -methylchalcone OH - OH CH​3 ​- - - OH - - - -


TPT Cushnie, AJ Lamb / Jurnal Internasional Agen Antimikroba 26 (2005) 343-356 3​ 47

Tabel 1 (​Lanjutan​)

Senyawa Substituen pada positio karbon n:

234567823456

Flavan-3,4-diol dan antosianidin


Leucocyanidin - OH OH OH - OH - - OH OH - - Pelargonidin klorida - Cl - OH - OH - - - OH - -

Flavan
6,4 -Dichloroflavan - - - - Cl - - - - Cl - - 7-Hydroxy-3, 4 - (methylenedioxy) flavan - - - - - OH - - # # - -

R1: Asam Glucuronic; R2: glukosa; R3: grup prenyl; R4: arabinose-galactose; R5: (2 -galloyl) -​α​-​L​-arabinopyranoside; R6: rhamnose; R7:
rhamnose-glukosa; R8: asam galat; R9: octanoyl; R10: lavandulyl; R11: 3-metil-1-butena. -, tidak ada substitusi; *, cincin piringan antara posisi 2

dan 3; #, O-CH​2​-O antara posisi 3 dan 4. ​Catatan:​ Hinokiflavone dan robustaflavone adalah biflavonoid (juga dikenal sebagai biflavonil) yang
terdiri dari dua molekul apigenin yang bergabung melaluiI-6-​O​ikatan-II-4 dan I-6-II-3.
bertanggung jawab besar atas efek antimikroba
Sifat antimikroba propolis telah dikaitkan dengan tanaman ini ​[28]​.
kandungan flavonoid yang tinggi dan khususnya
kehadiran flavonoid galangin dan pinocembrin
[12,25-27]​. Huang-chin (​Scutellaria baicalensis)​ 5. Toksisitas flavonoid
adalah contoh lain. Obat herbal ini telah digunakan
secara sistemik dan topikal selama ribuan tahun di Telah disarankan bahwa karena flavonoid
Cina untuk pengobatan abses periodontal dan luka didistribusikan secara luas dalam tanaman dan
mulut yang terinfeksi. Flavone baicalein dilaporkan minuman yang dapat dimakan dan sebelumnya telah
digunakan dalam pengobatan tradisional, mereka tamarii​,​A. flavus,​ ​Cladosporium sphaerospermum,​
kemungkinan memiliki toksisitas minimal. Namun, Penicillium digitatum d​ an ​Penicillium italicum [​ 35]​.
rangkaian senyawa ini memiliki beragam aktivitas
dalam sel mamalia ​[14,20] ​dan konfirmasi in vivo
efek sampingnya akan diperlukan untuk evaluasi 7. Aktivitas antivirus dari flavonoid
penuh kegunaan praktisnya dalam bidang kedokteran
modern ​[29]​. Mengingat bahwa selektivitas Suatu bidang penelitian terbaru yang sangat menarik
flavonoid untuk enzim eukariotik tampaknya adalah aktivitas penghambatan yang jelas dari
bervariasi dari senyawa ke senyawa ​[15,20]​, beberapa flavonoid terhadap human
penelitian semacam itu perlu menilai toksisitas immunodeficiency virus (HIV). Sampai saat ini,
fitokimia ini secara individual. sebagian besar jika tidak semua investigasi
melibatkan kerja dengan pandemi HIV-1 dan
enzim-enzimnya. Penelitian in vitro menunjukkan
6. Aktivitas antijamur flavonoid bahwa baicalin menghambat infeksi dan replikasi
HIV-1. Penghambatan masuknya HIV-1 ke dalam sel
Karena kemampuan luas flavonoid untuk yang mengekspresikan reseptor CD4 dan kemokin
menghambat perkecambahan spora patogen tanaman, [36]​, dan antagonisme transkrip terbalik HIV-1 ​[37]
mereka telah diusulkan untuk digunakan melawan oleh flavone ​O-​ glycoside telah ditunjukkan oleh Li
jamur patogen manusia ​[15]​. Flavanon terprenilasi dan rekan. Baicalein ​[38]​, robustaflavone dan
baru-baru ini diisolasi dari semak ​Eysen-hardtia hinokiflavone ​[39] ​juga telah terbukti menghambat
texana ​telah diidentifikasi sebagai 5,7,4 transkriptase balik HIV-1, seperti halnya beberapa
-trihydroxy-8- methyl-6- (3-methyl- [2-butenyl]) - katekin, tetapi katekin menghambat polimerase DNA
(2​S​) -flavanone dan terbukti memiliki aktivitas lain dan interaksinya dengan enzim HIV-1 dianggap
melawan patogen oportunistik ​Candida albicans tidak spesifik di alam ​[40]​. Selain itu, telah
[30]​. Flavonoid 7-hydroxy-3, 4 - (methylenedioxy) ditunjukkan bahwa beberapa flavonoid, termasuk
flavan, diisolasi dari ​Terminalia bellerica ​kulit buah, demetilasi gardenin A dan 3,2 -dihydroxyflavone,
juga telah terbukti memiliki aktivitas melawan ​C. menghambat HIV-1 proteinase ​[41]​. Robi- netin,
albicans[​ 31]​. Dua flavon baru dari​Artemisia giraldi​, myricetin, baicalein, quercetagetin ​[42] ​dan quercetin
diidentifikasi sebagai 6,7,4 -trihydroxy-3, 5 3-​O-​ (2 -galloyl) -​α​-​L​-arabinopyranoside ​[43]
-dimethoxyflavone dan 5,5 - dihydroxy-8,2, 4 menghambat integrase HIV-1, walaupun ada
-trimethoxyflavone, bersama dengan 5,7,4 - kekhawatiran bahwa enzim HIV terlibat oleh
trihydroxy-3 , 5 -dimethoxyflavone telah dilaporkan quercetagetin dan myricetin tidak spesifik ​[44]​. Juga
menunjukkan aktivitas melawan ​Aspergillus flavus telah dilaporkan bahwa flavonoid chrysin, acacetin
[32]​, suatu spesies jamur yang menyebabkan dan apigenin mencegah aktivasi HIV-1 melalui
penyakit invasif pada pasien dengan imunosupresi mekanisme baru yang mungkin melibatkan
[33]​. Aktivitas propolis terhadap dermatofita dan penghambatan transkrip virus ​[45]​. Menariknya,
Candida s​ pp. telah dikaitkan setidaknya sebagian dalam sebuah studi oleh Hu dan rekannya, chrysin
karena kandungan flavonoid yang tinggi ​[34]​. dilaporkan memiliki indeks terapi tertinggi dari 21
Galangin, flavonol yang umum ditemukan dalam flavonoid alami dan 13 sintetis terhadap HIV-1 ​[46]​.
sampel propolis ​[24]​, telah terbukti memiliki
aktivitas penghambatan terhadap​Aspergillus
348 ​TPT Cushnie, AJ Lamb / Jurnal Internasional Agen Antimikroba 26 (2005) 343-356
memiliki aktivitas melawan HSV dan virus
Beberapa kelompok penelitian telah menyelidiki coxsackie B ​[48,49]​. Juga telah dibuktikan bahwa
hubungan antara struktur flavonoid dan aktivitas dua flavonoid yang ditemukan dalam propolis,
penghambatan terhadap HIV-1 dan enzim-enzimnya chrysin dan kaempferol, menghambat replikasi virus
[39,41,42,44,46]​. Lebih lanjut, setidaknya dua HSV, human coronavirus dan rotavirus ​[50]​.
kelompok telah mengusulkan mekanisme aksi untuk Baru-baru ini, flavonol galangin telah dilaporkan
penghambatan enzim HIV-1 ​[41,42]​. memiliki aktivitas antivirus yang signifikan terhadap
Flavonoid juga memiliki aktivitas penghambatan virus HSV dan coxsackie B ​[51]​.
terhadap berbagai virus lainnya. Sebagai contoh, Walaupun flavonoid yang terjadi secara alami
Selway melaporkan bahwa quercetin, morin, rutin, dengan aktivitas antivirus telah dikenali sejak tahun
dihydroquercetin, dihydrofisetin, leucocyani- din, 1940-an, hanya dalam 25 tahun terakhir upaya telah
pelargonidin chloride dan catechin memiliki aktivitas dilakukan untuk secara sintetik memodifikasi
melawan hingga tujuh jenis virus, termasuk virus flavonoid untuk meningkatkan aktivitas antivirus.
herpes simpleks (HSV), virus sinkronisasi Salah satu senyawa yang disintesis tersebut adalah
pernapasan, poliovirus, dan Sindrom. virus bis 6,4 -dichloroflavan. Namun, meskipun menunjukkan
[11,47]​. Mekanisme aksi antivirus yang diusulkan aktivitas in vitro yang kuat, senyawa ini terbukti
termasuk penghambatan viral polimerase dan tidak berhasil dalam uji klinis ​[11]​.
pengikatan asam nukleat virus atau protein kapsid Sinergisme telah ditunjukkan antara berbagai
virus ​[47]​. Selain flavonoid yang disebutkan di atas, kombinasi flavon dan flavonol. Misalnya,
tiga proanthocyanidins dari ​Pavetta owariensis kaempferol dan luteolin menunjukkan sinergi
(dengan kemiripan struktural dengan proantosianidin melawan HSV. Telah dikemukakan bahwa inilah
A2 dan cinnamtannin B1 dan B2) telah terbukti sebabnya propolis lebih aktif daripada senyawa
komponennya masing-masing ​[52]​. Sinergisme juga isoflavon ​[115]​, flavonol ​[74.114.117]​, flavonol
telah dilaporkan antara flavonoid dan agen antivirus glikosida ​[86.118-120] ​dan chalcone
lainnya. Quercetin, misalnya, mempotensiasi efek [79.104.111.121] ​dengan aktivitas antibakteri juga
5-etil-2 -dioxyuridine ​[11] ​dan asiklovir ​[53] telah diidentifikasi.
terhadap HSV dan infeksi pseudorabies. Apigenin Beberapa peneliti telah melaporkan sinergi antara
juga meningkatkan aktivitas antivirus asiklovir flavonoid yang terjadi secara alami dan agen
terhadap virus ini ​[53]​. antibakteri lainnya terhadap strain bakteri yang
resisten. Contohnya termasuk epicatechin gallate
[122-125] ​dan sophoraflavanone G ​[83,84]​.
8. Aktivitas antibakteri flavonoid Setidaknya satu kelompok telah menunjukkan sinergi
antara flavonoid dengan aktivitas antibakteri ​[126]​.
8.1. Laporan flavonoid yang memiliki aktivitas Yang lain telah memodifikasi flavon alami secara
sintetis dan menganalisanya untuk aktivitas
antibakteri Aktivitas antibakteri flavonoid semakin antibakteri ​[94.127–131]​. Sebagai contoh, Wang dan
banyak didokumentasikan. Ekstrak kasar dari rekannya telah mengomplekskan 5-hidroksi-7,4
tanaman dengan riwayat penggunaan dalam -dimethoxyflavone dengan sejumlah logam transisi
pengobatan tradisional telah disaring secara in vitro dan menunjukkan bahwa proses ini meningkatkan
untuk aktivitas antibakteri oleh banyak kelompok aktivitas antibakteri ​[130]​. Kelompok lain
penelitian. Ekstrak tumbuhan kaya flavonoid dari melaporkan peningkatan aktivitas antibakteri
spesies ​Hypericum [​ 54]​, ​Capsella [​ 55] ​dan 3-methyleneflavanones ketika cincin B mengandung
Chromolaena ​[55] ​telah dilaporkan memiliki substituen bromin atau klorin ​[131]​. Dua kelompok
aktivitas antibakteri. Banyak preparasi fitokimia penelitian telah menggambarkan penggunaan
lainnya dengan kandungan flavonoid yang tinggi flavonoid in vivo. Dalam sebuah studi oleh Vijaya
juga telah dilaporkan menunjukkan aktivitas dan Ananthan, pemberian oral baik 142,9 mg / kg
antibakteri ​[22,56-63]​. Propolis juga telah quercetin atau 214,3 mg / kg quercetrin yang
dianalisis pada banyak kesempatan, dan sampel yang diproteksi guinea pigs terhadapdiinduksi ​Shigella
mengandung flavonoid konsentrasi tinggi sering yang i​ nfeksiyang membunuh hewan kontrol yang
dilaporkan menunjukkan aktivitas antibakteri tidak diobati ​[132]​. Baru-baru ini, Dasti dan rekan
[12,25-27,50,64]​. kerja melaporkan bahwa injeksi intraperitoneal dari
Banyak kelompok penelitian telah melangkah lebih 1,58mg / kg sophoraisoflavone A atau 3,16mg / kg
jauh dan mengisolasi dan mengidentifikasi struktur 6,8-diprenylgenistein memberikan perlindungan
flavonoid yang memiliki aktivitas antibakteri, atau yang signifikan terhadap tikus yang ditantang dengan

mengukur aktivitas flavonoid yang tersedia secara ∼​9,5​×​10​8 unit pembentuk koloni (CFU) dari
komersial. Contoh flavonoid tersebut adalah apigenin Salmonella typhimurium ​[110]​.
[65-73]​, galangin ​[35,74-77]​, pinocembrin ​[78,79]​,
ponciretin ​[80,81]​, genkwanin ​[66,82]​, 8.2. Perbedaan antara laporan aktivitas antibakteri
sophoraflavanone G dan turunannya ​[29, 83-85]​, flavonoid
naringin dan naringenin ​[29,60,86,87]​,
epigallocatechin gallate dan turunannya ​[74,88-95]​, Ketika laporan aktivitas antibakteri flavonoid
luteolin dan luteolin 7- glucoside ​[69,73,96]​, dibandingkan, hasilnya tampak sangat bertentangan
quercetin, 3-​O-​ methylquercetin dan berbagai (​Tabel 2​). Sebagai contoh, itu diterbitkan bahwa
quercetin glikosida ​[60,65,72,87,97-102] ​dan apigenin tidak memiliki aktivitas terhadap ​S. aureus
kaempferol dan turunannya pada konsentrasi hingga 128​μ​g / mL ​[72];​sebuah
[60,65,74,76,76,87,98,100,103]​. Flavon lain studi terpisah pada tahun yang sama melaporkan
[32,60,74,104-107]​, sisiflavon ​glikol[86,108,109]​, bahwa flavone menghambat pertumbuhan 15 galur
isoflavon ​[110,111]​, flavanon MRSA dan 5 galur ​S. aureus ​dengan konsentrasi
[29,30,78,79,104,111-1111]​, isoflavanon ​[115]​, antara 3,9​μg​ / mL
TPT Cushnie, AJ Lamb / Jurnal Internasional Agen Antimikroba 26 ( 2005) 343-356 3​ 49

2 elba​ 0 002dna0891neewtebspuorghcraesersuoiravybdenimretedsa,
T​
airetcabevitagen-marGdnaevitisop-marGfoseicepssuoremuntsniaganinegipafoytivitcayrotibihnieh​
T​dan 15,6​μ​g / mL [​ 73].​Dari ​Tabel 2
dapat dilihat bahwa perbedaan tersebut mungkin dapat dikaitkan pada kesempatan untuk tes yang berbeda yang
digunakan (misalnya ​[65,70] ​dan ​[72,73]​). Banyak pengujian yang berbeda digunakan dalam penelitian flavonoid,
termasuk teknik pengenceran agar ​[29]​, uji difusi cakram kertas ​[115]​, metode difusi lubang-pelatmetode difusi
[22]​,silinder ​[60]​, metode produksi kaldu teknik ​[71] ​dan teknik mikrodilusi kaldu ​[134]​. Secara khusus, tes yang
mengandalkan difusi flavonoid uji mungkin tidak memberikan ukuran kuantitatif yang dapat diandalkan dari
aktivitas antibakteri karena flavonoid antibakteri yang kuat mungkin memiliki tingkat difusi yang rendah ​[32]​.
Namun, jelas dari ​Tabel 2 ​bahwa faktor-faktor tambahan terlibat dalam menyebabkan perbedaan ini karena bahkan
kelompok yang menggunakan pengujian yang sama mendapatkan hasil yang bertentangan (misalnya ​[67,96] ​dan
[67,72]​). Ketidakkonsistenan tersebut mungkin disebabkan oleh variasi dalam setiap pengujian. Sebagai contoh,
kelompok yang berbeda menggunakan teknik pengenceran agar telah menggunakan berbagai ukuran inokulum
bakteri ​[81,86]​. Dalam sebuah laporan oleh Komite Nasional untuk Standar Laboratorium Klinis (NCCLS), ukuran
inokulum dianggap sebagai variabel paling penting dalam pengujian kerentanan ​[135]​. Perlu dicatat bahwa banyak
kelompok yang menguji aktivitas antibakteri flavonoid belum mengukur suspensi bakteri uji ​[60.115] ​dan yang lain
bahkan belum menstandardisasi ukuranmereka yang tidak ​inokuladihitung [35,56,76,90,97]​. Dari karya yang
dipublikasikan jelas bahwa, selain ukuran inokulum, ada banyak faktor variabel lain untuk setiap jenis pengujian. Ini
termasuk volume kaldu atau agar ​[90.116]​, jenis kaldu atau agar ​[86,92]​, ukuran sumur ​[56,60]​, ukuran cakram
kertas ​[57,65]​, strain dari spesies bakteri tertentu yang digunakan ​[69,72] ​dan masa inkubasi ​[90,116]​. Baru-baru ini,
seperangkat pedoman diterbitkan untuk pengenceran agar standar, makrodilusi kaldu dan metode mikrodilusi kaldu
[136]​. Ini dapat membantu mengurangi jumlah laporan yang saling bertentangan tentang aktivitas antibakteri
flavonoid di masa depan. Namun, tetap perlu untuk mempertimbangkan dengan hati-hati variabel tambahan seperti
pelarut yang digunakan untuk melarutkan uji flavonoid ​[116.118]​. Sebelumnya telah ditunjukkan bahwa presipitasi
terjadi ketika flavonoid terpilih dilarutkan dalam pelarut organik dan diencerkan dengan larutan netral polar ​[75]​.
Pengendapan flavonoid dalam uji konsentrasi hambat minimum (MIC) cenderung menyebabkan berkurangnya
kontak antara sel-sel bakteri dan molekul flavonoid dan dapat menyebabkan laporan negatif palsu dari aktivitas
antibakteri. Juga, dalam percobaan yang dikendalikan secara tidak benar, presipitasi flavonoid dapat disalahartikan
sebagai pertumbuhan bakteri dan selanjutnya hasil negatif palsu dapat dicatat sebagai konsekuensinya. Perubahan
struktural flavonoid seperti galangin dalam pelarut alkali adalah masalah lain untuk dipertimbangkan ​[75]​. Jika
garam flavonoid terbentuk dan ini telah meningkatkan atau menurunkan potensi dibandingkan dengan struktur induk,
ini dapat menyebabkan laporan positif / negatif palsu dari aktivitas antibakteri. Variabel lain yang perlu diperhatikan
termasuk apakah tes flavonoid diperoleh dari sumber komersial atau alami ​[35,74] ​dan dari perusahaan manamana
[74,75]asalnya​/ produk alami ​[71,72] ​dari.

350 ​TPT Cushnie, AJ Lamb / Jurnal Internasional Agen Antimikroba 26 (2005) 343–356
phytochemicals may target different com- ponents
8.3. Hubungan struktur-aktivitas untuk aktivitas and functions of the bacterial cell ​[137–139]​. If this
antibakteri flavonoid is the case, it is surprising that the small number of
groups which have investigated the relationship
Berbagai fungsi sel yang dipengaruhi oleh flavonoid between flavonoid struc- ture and antibacterial
dalam sistem eukariotik didokumentasikan dengan activity (summarised below) have been able to
baik ​[10,20]​. Although there have been identify common structural features among active
comparatively few studies into the mecha- nisms compounds. However, it may be that individual
underlying flavonoid antibacterial activity, antibacte- rial flavonoids have multiple cellular
information from published literature indicates that targets, rather than one specific site of action.
different compounds within this class of Alternatively, these common structural features may
simply be necessary for flavonoids to gain prox- supporting the earlier findings of
imity to or uptake into the bacterial cell. Tsuchiya et al. ​[29]​. It further states that chalcones
Tsuchiya and colleagues sought to establish a are more effective against MRSA than flavanones or
structure– activity relationship for flavanones by flavones, and that hydroxyl groups at the 2 position
isolating a number of differently substituted are important for the anti- staphylococcal activity of
compounds and determining their MICs against these compounds. Methoxy groups were reported to
MRSA ​[29]​. Their study indicated that 2 ,4 - or 2 ,6 drastically decrease the antibacterial activ- ity of
-dihydroxylation of the B ring and flavonoids ​[104]​. The importance of hydroxylation at
5,7-dihydroxylation of the A ring in the flavanone the 2 position for antibacterial activity of chalcones
structure was important for anti-MRSA activity. is supported by earlier work from Sato and
Substitution at the 6 or 8 position with a long chain colleagues, who found that 2,4,2 -trihydroxy-5
aliphatic group such as lavandulyl (5-methyl-2- -methylchalcone and 2,4,2 - trihydroxychalcone
isopropenyl-hex-4-enyl) or geranyl inhibited the growth of 15 strains of cariogenic
(trans-3,7-dimethyl-2,6- octadienyl) also enhanced streptococci ​[140]​.
activity ​[29]​. Interestingly, a recent report by As mentioned previously, Ward and colleagues syn-
Stapleton and colleagues demonstrated that sub- thesised a number of halogenated derivatives of 3-
methyleneflavanone ​[131]​. Substitution of the B ring
stitution with C​8 ​and C​10 c​ hains also enhanced the
was found to enhance antibacterial activity, with 3
-chloro, 4 - chloro and 4 -bromo analogues each
anti- staphylococcal
​ activity of flavonoids belonging
being approximately twice as effective as their parent
to the flavan- 3-ol class ​[94]​.
compound against​S. aureus​, and four times more
Osawa et al. assessed the activity of a number of
active against ​Enterococcus faecalis.​ Also, the 2 ,4
struc- turally different flavonoids including flavones,
-dichloro derivative exhibited a four- to eight- fold
flavanones, isoflavones and isoflavanones based on
improvement in activity against ​S. aureus ​and a two-
the paper disk agar diffusion assay ​[115]​. It was
to four-fold improvement against ​E. faecalis​. By
shown that 5-hydroxyflavanones and
contrast, 3-methylene-6-bromoflavanone was less
5-hydroxyisoflavanones with one, two or three
potent than the par- ent compound and the authors
additional hydroxyl groups at the 7, 2 and 4 positions
suggested that halogenation of the A ring may
inhibited the growth of ​Streptococcus mutans a​ nd
diminish activity ​[131]​. Clearly, however, it would
Streptococcus sobrinus.​ These results correlate well
be necessary to prepare analogues with substitu- tion
with those of Tsuchiya and col- leagues ​[29]​. It was
at other A-ring positions before this could be said
also reported by Osawa and colleagues that
with any certainty. In chalcones, neither fluorination
5-hydroxyflavones and 5-hydroxyisoflavones with
nor chlo- rination at position 4 of the B ring is
addi- tional hydroxyl groups at the 7 and 4 positions
reported to affect antibacterial potency significantly
did not exhibit this inhibitory activity ​[115]​.
[104]​. Again, however, other structural analogues of
However, when Sato et al. exam- ined two
this class of flavonoids would need to be synthesised
isoflavones with hydroxyl groups at the 5, 2 and 4
and examined before the effect of halogenation upon
positions using an agar dilution assay, intensive
antibacterial activity could be properly assessed.
inhibitory activity was detected against a wide range
of streptococcal species ​[107]​. This may suggest that
8.4. Nature of flavonoid activity: bacteriostatic or
hydroxylation at position 2 is important for activity.
bactericidal?
Alternatively, the lack of activity detected by Osawa
et al. may simply be due to the poor diffu- sion of
Several research groups have attempted to determine
flavones and isoflavones (compared with flavanones
whether flavonoid activity is bacteriostatic or
and isoflavanones) through the medium.
bactericidal by conducting time–kill studies. In such
A more recent paper ​[104] ​also reports the experiments, epi- gallocatechin gallate ​[89]​, galangin
importance of a hydroxyl group at position 5 of [75] ​and 3-​O-​ octanoyl- (+)-catechin ​[94] ​have been
flavanones and flavones for activity against MRSA,
shown to cause a reduction of 1000-fold or more in phe- nomenon is induced by other compounds within
viable counts of MRSA-YK, ​S. aureus ​NCTC 6571 the flavonoid class (and liposomal studies suggest
and EMRSA-16, respectively. This would imme- that this is the case for epigallocatechin gallate ​[88]​),
diately appear to suggest that flavonoids are capable questions are raised regarding the interpretation of
of bac- tericidal activity. However, it has recently results from time–kill studies. It may be that
been demonstrated that 3-​O-​ octanoyl-(​−)​ -epicatechin flavonoids are not killing bacterial cells but merely
induces the formation of pseudomulticellular inducing the formation of bacterial aggregates and
aggregates both in antibiotic-sensitive and thereby reducing the number of CFUs in viable
antibiotic-resistant strains of ​S. aureus [​ 94]​. If this counts.

TPT Cushnie, AJ Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 3​ 51


hydrogen bonding with the stacking of nucleic acid
8.5. Antibacterial mechanisms of action of various bases and that this may explain the inhibitory action
flavonoids on DNA and RNA synthesis ​[138]​.
Ohemeng et al. screened 14 flavonoids of varying
8.5.1. Inhibition of nucleic acid synthesis struc- ture for inhibitory activity against ​Escherichia
In a study using radioactive precursors, Mori and col- coli D ​ NA gyrase, and for antibacterial activity
leagues showed that DNA synthesis was strongly against ​Staphylococ- cus epidermidis,​ ​S. aureus,​ ​E.
inhibited by flavonoids in ​Proteus vulgaris,​ whilst coli,​ ​S. typhimurium ​and ​Stenotrophomonas
RNA synthesis was most affected in ​S. aureus [​ 138]​. maltophilia [​ 68]​. It was found that ​E. coli ​DNA
Flavonoids exhibiting this activity were robinetin, gyrase was inhibited to different extents by seven of
myricetin and (​−​)-epigallocatechin. Protein and lipid the compounds, including quercetin, apigenin and
synthesis were also affected but to a lesser extent. 3,6,7,3 ,4 - pentahydroxyflavone. Interestingly, with
The authors suggested that the B ring of the the exception of 7,8-dihydroxyflavone, enzyme
flavonoids may play a role in intercalation or inhibition was limited to those compounds with
B-ring hydroxylation ​[68,141]​. The authors proposed position 410 of the GrlB subunit. This may suggest
that the observed antibacterial activity of the seven that topoisomerase IV and the relatively homologous
flavonoids was due in part to their inhibition of DNA gyrase enzyme are involved in the antibacterial
gyrase. However, since the level of antibacterial mechanism of action of galangin. Clearly, however,
activity and enzyme inhibition did not always further work with mutant strains and purified
correlate, they also suggested that other mechanisms enzymes would be necessary before this could be
verified.
were involved ​[68]​.​More recently, Plaper and

8.5.2. Inhibition of cytoplasmic membrane function


colleagues reported that ​quercetin binds to the GyrB
subunit of​E. coli​DNA gyrase and inhibits the A research team that had previously found
enzyme's ATPase activity ​[142]​. Enzyme binding sophorafla- vanone G to have intensive antibacterial
was demonstrated by isolating ​E. coli D ​ NA gyrase activity against MRSA and streptococci ​[83–85]
and mea- suring quercetin fluorescence in the recently reported attempts to elucidate the
presence and absence of the gyrase subunits. The mechanism of action of this flavanone ​[139]​. The
flavonoid-binding site was pos- tulated to overlap effect of sophoraflavanone G on membrane flu- idity
with those of ATP and novobiocin, since addition of was studied using liposomal model membranes and
these compounds interfered with quercetin fluo- compared with the less active flavanone naringenin,
rescence. Inhibition of GyrB ATPase activity by which lacks 8-lavandulyl and 2 -hydroxyl groups. At
quercetin was also demonstrated in a coupled concentra- tions corresponding to the MIC values,
ATPase assay. This research is in agreement with the sophoraflavanone G was shown to increase
earlier findings of Ohe- meng et al. ​[68] ​and supports fluorescence polarisation of the liposomes
the suggestion that quercetin's antibacterial activity significantly. These increases indicated an alter-
against ​E. coli ​may be at least partially attributable to ation of membrane fluidity in hydrophilic and
inhibition of DNA gyrase. hydrophobic regions, suggesting that
When screening natural products for type II sophoraflavanone G reduced the flu- idity of outer
and inner layers of membranes. Naringenin also
topoisomerase inhibitors, Bernard and co-workers
exhibited a membrane effect but at much higher con-
found that the glycosy- lated flavonol rutin was very
centrations. This correlation between antibacterial
effective ​[143]​. This compound exhibited
activity and membrane interference was suggested to
antibacterial activity against a permeable ​E. coli
support the theory that sophoraflavanone G
strain (a strain into which the ​envA1 a​ llele had been
demonstrates antibacterial activity by reducing
incor- porated ​[144,145]​). Using enzyme assays and
membrane fluidity of bacterial cells ​[139]​.
a technique known as the SOS chromotest, it was
shown that rutin selec- tively promoted ​E. coli Another group, Ikigai and colleagues, carried out
topoisomerase IV-dependent DNA cleavage, research on (​−​)-epigallocatechin gallate, a strongly
inhibited topoisomerase IV-dependent decatena- tion antibacterial cat- echin found in green tea. Catechins
activity and induced the SOS response of the ​E. coli are a group of flavonoids that appear to have greater
strain. The group suggested that since topoisomerase activity against Gram-positive than Gram-negative
IV is essential for cell survival, the rutin-induced bacteria ​[88]​. In this study, liposomes were again
topoisomerase used as model bacterial membranes, and it was
IV-mediated DNA cleavage leads to an SOS shown that epigallocatechin gallate induced leakage
response and growth inhibition of ​E. coli ​cells [​ 143]​. of small molecules from the intraliposomal space.
Within our own laboratory, a 4-quinolone-resistant ​S. Aggregation was also noted in liposomes treated with
the compound. The group therefore concluded that
aureus s​ train was shown to have increased
catechins primarily act on and damage bacterial
susceptibility to the flavonol galangin compared with
membranes. It was not known how this damage
other 4-quinolone- sensitive and -resistant strains
occurred but two theories were put forward. First,
[146]​. Interestingly, this strain possesses a distinct
catechins may perturb the lipid bilayers by directly
amino acid substitution (serine to pro- line) at
penetrating them and disrupting the barrier function. leakage induced by epigallocatechin gallate was
Alterna- tively, catechins may cause membrane significantly lower when liposome membranes were
fusion, a process that results in leakage of prepared containing nega- tively charged lipids. It
intramembranous materials and aggrega- tion. was therefore suggested that the low catechin
Interestingly, the group also demonstrated that susceptibility of Gram-negative bacteria may be at

352 ​TPT Cushnie, AJ Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356
were shown to form pseudomulti- cellular aggregates
least partially attributable to the presence of [94]​. This work constitutes a substantial advance in
lipopolysaccha- ride acting as a barrier ​[88]​. the development of catechins as antibacterial agents
As mentioned previously, Stapleton and colleagues and lends support to Ikigai's argument that catechins
act on and damage bacterial membranes.
found that substitution with C​8 a​ nd C​10 c​ hains
It has also been demonstrated by Sato and colleagues
that the chalcone 2,4,2 -trihydroxy-5
increased the antibac- terial
​ activity of selected
-methylchalcone induces leakage of 260nm
flavan-3-ols (catechins). The group went on to show
absorbing substances from ​S. mutans.​ This
that cells of an MRSA clinical isolate treated with
observation generally indicates leakage of
(​−​)-epicatechin gallate and
intracellular material such as nucleotide, and the
3-​O-​ octanoyl-(+)-catechin, respectively, exhibited
authors suggested that 2,4,2 -trihydroxy-5
moderately and highly increased lev- els of labelling
-methylchalcone exerts its antibacterial effect by
with the selectively permeable fluorescent stain
changing the permeability of the cellular membrane
propidium iodide. In addition, when​S. aureusc​ ells
and damaging membrane function ​[140]​.
were grown in the presence of either (​−​)-epicatechin
In addition, the effect of galangin upon cytoplasmic
gallate or 3- ​O​-octanoyl-(​−​)-epicatechin and
examined by transmission electron microscopy, they integrity in ​S. aureus ​has been investigated by
measuring loss of internal potassium ​[147]​. When investi- gation into the antibacterial mode of action
high cell densities of ​S. aureus ​were incubated for of two retrochal- cones (licochalcone A and C) from
12h in media containing 50​μ​g/mL of the flavonol, a the roots of ​Glycyrrhiza inflata​[137]​. These
60-fold decrease in the number of CFUs was noted flavonoids demonstrated inhibitory activ- ity against
and cells lost ca. 20% more potassium than untreated S. aureus a​ nd ​Micrococcus luteus ​but not against ​E.
control bacteria. These data strongly suggest that coli,​ and in preliminary tests licochalcone A
galangin induces cytoplasmic membrane damage and inhibited incorporation of radioactive precursors into
potassium leakage. Whether galangin damages the macromolecules (DNA, RNA and protein). The
mem- brane directly, or indirectly as a result of group hypothesised that the licochalcones may be
autolysis or cell wall damage and osmotic lysis, interfering with energy metabolism in a similar way
remains to be established however ​[147]​. to respiratory-inhibiting antibiotics, since energy is
In an investigation into the antimicrobial action of required for active uptake of various metabolites and
propo- lis, Mirzoeva and colleagues showed that one for biosynthesis of macromolecules ​[137]​.
of its con- stituent flavonoids, quercetin, caused an Interestingly, the licochalcones were found to inhibit
increase in perme- ability of the inner bacterial strongly oxygen con- sumption in ​M. luteus ​and ​S.
membrane and a dissipation of the membrane aureus b​ ut not in ​E. coli​, which correlated well with
potential ​[148]​. The electrochemical gradient of the observed spectrum of antibacterial activity. The
protons across the membrane is essential for bacteria group further demonstrated that licochalcones A and
to maintain capacity for ATP synthesis, membrane C effectively inhibited NADH-cytochrome ​c r​ educ-
transport and motility. Mirzoeva et al. suggested that tase, but not cytochrome ​c o​ xidase or NADH-CoQ
the effect of propo- lis on membrane permeability reductase. It was therefore suggested that the
and membrane potential may contribute enormously inhibition site of these retrochalcones was between
to its overall antibacterial activity and may decrease CoQ and cytochrome ​c ​in the bacterial respiratory
the resistance of cells to other antibacterial agents. It electron transport chain ​[137]​.
was thought that this might explain the synergistic Merck Research Laboratories recently reported that
effect that occurs between propolis and other the flavanone lonchocarpol A inhibits
antibiotics such as tetracycline ​[148] ​and ampicillin macromolecular synthesis in ​Bacillus megaterium.​
[149]​. The group also demonstrated that the Using radioactive precursors, it was demonstrated
flavonoids quercetin and naringenin significantly that RNA, DNA, cell wall and protein synthesis were
inhibited bacterial motility, providing further all inhibited at concentrations similar to the MIC
evidence that the proton motive force is disrupted. value ​[150]​. This may represent another example of a
Bacte- rial motility and chemotaxis are thought to be flavonoid that interferes with energy metabolism.
important in virulence as they guide bacteria to their
sites of adherence
and invasion. Mirzoeva et al. suggested that the 9. Concluding remarks
antimotil- ity action of propolis components may
have an important role in inhibition of bacterial With regard to natural products, it is generally
pathogenesis and the develop- ment of infection accepted that phytochemicals are less potent
[148]​. The cytoplasmic membrane activ- ity detected anti-infectives than agents of microbial origin, ie
for quercetin by Mirzoeva and co-workers may antibiotics ​[48]​. However, new classes of
represent one of the additional mechanisms of antimicrobial drug are urgently required and the
antibacterial action that was suspected to be present flavonoids represent a novel set of leads. Future
among the seven DNA gyrase-inhibiting flavonoid optimisation of these compounds through structural
compounds tested by Ohemeng and colleagues ​[68]​. alteration may allow the devel- opment of a
pharmacologically acceptable antimicrobial agent or
8.5.3. Inhibition of energy metabolism group of agents. Existing structure–activity data
Haraguchi and colleagues recently carried out an suggest that it might be possible, for example, to
prepare a potent antibacterial flavanone by the A ring. Also, it is worth noting that the rapid
synthesising a compound with halogenation of the B progress which is being made toward elucidation
ring as well as lavandulyl or ger- anyl substitution of

TPT Cushnie, AJ Lamb / International Journal of Antimicrobial Agents 26 (2005) 343–356 3​ 53

of flavonoid biosynthetic pathways ​[151] ​may soon


allow the production of structural analogues of active Acknowledgments
flavonoids through genetic manipulation. Screening
of these analogues might lead to the identification of The authors are very grateful to Dr Paul Kong and Dr
compounds that are suffi- ciently potent to be useful Satyajit Sarker for critiquing preliminary drafts of the
as antifungal, antiviral or antibac- terial manuscript and for advice on flavonoid classification
chemotherapeutics. In addition to the structural alter- and structure. Thanks are extended to Dr Peter
ation of weak and moderately active antimicrobial Taylor for insight- ful comments regarding
flavonoids, investigation into the mechanisms of interpretation of data from time–kill studies with
action of these com- pounds is likely to be a flavonoids. Thanks also to Dr Derek Chapman, Miss
productive area of research. Such information may Vivienne Hamilton, Dr Bruce Thomson and Mrs
assist in the optimisation of a lead com- pound's Amina Al-Mossawi for their kind support and
activity, provide a focus for toxicological attention encouragement.
and aid in the anticipation of resistance. Also,
characterisa- tion of the interaction between
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Erratum ​Errata for “Antimicrobial activity of flavonoids” [Int. J.


Antimicrob. Agents 26 (2005) 343–356]
TP Tim Cushnie, Andrew J. Lamb​∗
School of Pharmacy, The Robert Gordon University, Schoolhill, Aberdeen AB10 1FR, UK

Errors occurred during typesetting of ​Table 1 ​for the above review article. The flavonol morin has hydroxyl groups at
positions 3, 5, 7, 2 and 4 (not 3, 7, 2 , 4 and 5 ), and the flavan-3-ol catechin has hydroxyl groups at positions 3, 5, 7,
3 and 4 (not 3, 4, 7, 3 and 5 ). The structures of these compounds should have been given in ​Table 1 ​as shown below.

Table 1 A summary of the structures of antimicrobial flavonoids discussed within the present review article (compiled from The Handbook of
Natural Flavonoids and individual research papers)

Compound Substituents at carbon position

234567823456

Flavonols and their glycosides: Morin – OH – OH – OH – OH – OH – – Flavan-3-ols: Catechin – OH – OH – OH – – OH OH – –

DOI of original article:10.1016/j.ijantimicag.2005.09.002. ​∗ ​Penulis yang sesuai. Tel.: +44 1224 262526.
E-mail addresses: t​ .cushnie@rgu.ac.uk (TPT Cushnie), a.lamb@rgu.ac.uk (AJ Lamb).

0924-8579/$ – see front matter © 2005 Elsevier BV and the International Society of Chemotherapy. Seluruh hak cipta.
doi:10.1016/j.ijantimicag.2005.12.002
International Journal of Antimicrobial Agents 27 (2006) 181