Antibiotik &

mekanisme
Resistensi

dr. Yani Sodiqah, M.Kes

Bagian Mikrobiologi
Fakultas Kedokteran
Universitas Muslim Indonesia
 ANTIBIOTIK
 Zat kimia yang dihasilkan oleh jamur atau bakteri
 Mematikan atau menghambat pertumbuhan kuman
 Toksisitas bagi manusia relatif kecil

SEJARAH
Penicillin ( jamur dari genus Penicillium), antibiotik pertama yg ditemukan
oleh Alexander Fleming pada tahun 1928 secara tidak sengaja.
Howard Florey dan Ernst Boris Chain memurnikan penicillin sebagai
antibiotic
 Resistensi
Terhambatnya pembunuhan bakteri dengan pemberian antibiotik, dosis normal
seharusnya/ kadar hambat minimalnya.

Superbugs is a name given to harmful bacteria that have

acquired resistance to one or more of the antibiotics used to
treat them
CDC,2019
O’Neil, J. (2014). Review on Antibiotic resisitance
CDC,2019
 Resistensi
antibiotik di
Indonesia

( Murray, C, 2022, Global burden of bacterial antimicrobial resistance in 2019, Lancet)

Iskandar, K, 2022
 Target dan Cara Kerja beberapa Antibiotik terhadap Bakteri

1. Menghambat sintesis dinding sel :

Dari subunit dinding sel 
melintasi sitoplasma  masuk ke
peptidoglikan yg sedang
berkembang (Beta laktam,
Penicylin, Polypeptida,
Sefalosforin, Ampycilin, Oxacylin)

peptidoglikan  pertahankan hidup

di lingkungan yang hipotonik.
Rusak/hilang hilangnya kekakuan
dinding sel  Mati
Menghambat fungsi membran sitoplasma
Merusak barier yg mengatur komposisi internal sel  makromolekul dan ion akan keluar
dari sel  sel mati (linomycin, Valinomycin)

Menghambat sintesis protein

Menghambat proses translasi mRNA ke protein di ribosom ( Macrolide, Aminoglycosid,
Chloramphenicol, Tetracyclin, Kanamycin, oxytetracyclin)

Menghambat sintesis asam nukleat

Ada 4 tingkat :
Hambat sintesis prekursor untuk asam nukleat (folat) :Sulfunamid, Trimetroprim
(antimetabolit)
Hambat aktivitas DNA : golongan quinolon : Nalidixid acyd, cyproloxacin, levofloxacin,
gati/ moxyfloxacin
Hambat RNA Polymerase : Rifampycin
Interferensi replikasi DNA : Metronidazole
Target dan Cara Kerja beberapa Antibiotik terhadap Bakteri
• Bakteri resisten antibiotik. Dikutip dari Levy , 1998)
 Resistance mechanisms

Pauter, K., Szultka-Młyńska, M., & Buszewski, B. (2020).


• rpoB gene mutation  MTB resistance to rifampicin
• MRSA  Alteration of Penicillin-Binding Proteins
(PBPs) as target of β-lactam antibiotics
• vancomycin, macrolides, lincosamides, and
streptavidin
• Antibiotik hidrofilik masuk Bakteri GN melalui
porin  OmpF, OmpC, and OmpE
• exposed to antibiotics more often  induced in
the structural gene encoding OmpF protein
reduction in, or loss of, OmpF channel protein
• P. aeruginosa  natural resistance to antibiotics
for many broad-spectrum antibacterial drugs
• accumulation of toxic compounds in cells  utilize
proton motive force (PMF) as an energy source by
pumping Na and hydrogen out of the membrane
• Tet pumps tetracyclines or Mef pumps macrolides
• MexAB-OprM  P. aeruginosa (intrinsic resistance to β-
lactams, chloramphenicol, tetracycline,
• trimethoprim, sulfamethoxazole, and some fluorine
Quinolones)

Iskandar, K, 2022
• Inactivating bacterial enzymes
• β -lactamase  carbonyl moiety bind disrupt cyclic
structure  degradation in the β -lactam antibiotic
before reaching the target  8 type  E. coli, K. pneu-
moniae,P. aeruginosa, A.baumannii
• Carbapenem-producing Enterobacteriaceae (CPE)
• NAD-dependent enzymesinactivate rifampicin
• long aliphatic carbon chain of the rifampicin structure.
Chloramphenicol acetyltransferases
• (CATs)  prevent chloramphenicol-ribosom binding
• S. aureus, Enterococcus faecium, M. tuberculosis, E. coli,
Salmonella. spp. and other bacteria
• mutations in core genes  sucA gene inhibiting
tricarboxylic acid cycle AB activity  reduces basal respiration 
avoiding the occurrence of metabolic toxicity  inhibiting the
killing effect of antibiotics
• Sulfonamides vs p-aminobenzoic acid (PABA)  bind to the active
site of dihydrofolate synthasein the process of bacterial folate
metabolism  inhibits the activity of dihydrofolate synthase
(DHFA &THFA)  prevents bacterial folate metabolism.
• Bacteria can weaken the inhibitory effect of sulfonamide on folic
acid metabolism through metabolism enhancement, & obtain
folic acid from extracellular in an auxotrophic way to maintain
normal metabolism
• tetracycline ribosomal protection proteins
(TRPPs)13 type
 changes in ribosome configuration, and directly
interfering with the interaction of tetracycline D-
ring and 16S rRNA base C1054
 Type II  lincomycins, macrolides, azadones,
phenols, pleuromutilins, and stroopogramins of
groups A and B
 Type III  S.aureus and other staphylococcus
 resistance to fusidic acid

• E. coli multiple antibiotic resistance (mar)
locus was recognized as a determinant for
cross-resistance to tetracyclines, quinolones
and -lactams
In Aaron’s study, the cell walls remained
intact, but stretched so violently that a “C”
shape was formed  feedback strategy to
enable it to adapt to the antibiotic
environment and survive
• autocrine polymer matrix

(1) collective drug resistance, that is, the interaction elevating the
MIC of the community;  P. aeruginosa  elicit the metabolic
transformation of S. aureus, inhibit its growth and provide S. aureus
with protection against vancomycin

(2) Collective tolerance, i.e., interactions within the community 

reduce the rate of cell death during antibiotic treatment without
increasing the MIC;  S. aureus promoting aggregation and altering
the biofilm structure  enhance the tolerance of P. aeruginosa to
tobramycin

(3) Contact protection reducing the effective MIC community In the

mixed biofilm  E. coli  indole  dependent multidrug efflux
pump in P. putida,
S. maltophilia generally appearing accompanied by P. aeruginosa
during bacterial lung infection diffuse the secretion of signal
factors, transform the biofilm structure of P. aeruginosa, and
stimulate the synthesis of protein
• Resistensi kuman >> kegagalan terapi antibiotik.

• Faktor mempengaruhi resistensi kuman:

 penggunaan antibiotik
 pengendalian infeksi.

• Lemahnya kontrol infeksi & penggunaan antibiotik

yang luas mempermudah penyebaran resistensi
Perubahan genetik
• mutasi,
• transduksi (transfer DNA melalui bakteriofaga)
• transformasi (DNA berasal dari lingkungan)
• konjugasi(DNA berasal dari kontak langsung bakteri
yang satu ke bakteri lain melalui plasmid)

Mutasi,transduksi dan transformasi : mekanisme yang

terutama berperan di dalam timbulnya resistensi
antibiotik pada bakteri kokus Gram positif.
Sedangkan pada bakteri batang Gram negatif semua
proses termasuk konjugasi bertanggung jawab dalam
timbulnyaresistensi (Sande, 1990)
Resistensi dengan perantaraan plasmid

Bakteri memperoleh gen resisten antibiotik. Dikutip dari Levy (1998)

 The Center for Disease
Berbagai studi Control & Prevention USA

40-62% antibiotik digunakan

tidak tepat
50 juta peresepan antibiotik
yang tidak diperlukan
penyakit yang sebenarnya (unnescecery prescribing)
tidak memerlukan antibiotik dari 150 juta peresepan
setiap tahun

• Resistensi kuman >> kegagalan terapi antibiotik.

• Faktor mempengaruhi resistensi kuman:
 penggunaan antibiotik
 pengendalian infeksi.
• Lemahnya kontrol infeksi & penggunaan antibiotik yang luas mempermudah penyebaran resistensi
 Doctor’s Dilemma

Naido, Wilson. Antibiotic Dilemma.2004

 I. Antibiotic selective pressure

Incomplete Treatment
Causes Resistance
Day 0

R
Day 3
X
R
X X Day 10
Antibiotics
X X RR
prescribed
RR
Symptoms improved,
R R

R
treatment stopped

Meanwhile, the
survivors multiply. Resistant
Fong, 2018.

(Adapted from Levin BR, Clin Infect Dis 2001)

PERATURAN MENTERI KESEHATAN REPUBLIK INDONESIA
NOMOR 28 TAHUN 2021 TENTANG
PEDOMAN PENGGUNAAN ANTIBIOTIK
 How to select antibiotic?

• Definitif AB  Kultur bakteri & AST

• Empiris  Pola Kuman setempat:
1. Faktor bakteri penyebab
2. Faktor pasien
3. Sifat PK/PD antibiotik
• O’Neil, J. (2014). Review on Antibiotic resisitance. Antimicrobial Resistance:
Tackling a crisis for the health and wealth of nations. Heal. Wealth Nations, 1-16.
• Fong, I. W., Shlaes, D., & Drlica, K. (Eds.). (2018). Antimicrobial resistance in the
21st century. Springer.
• Murray, C. J., Ikuta, K. S., Sharara, F., Swetschinski, L., Aguilar, G. R., Gray, A., ...
& Tasak, N. (2022). Global burden of bacterial antimicrobial resistance in 2019: a
systematic analysis. The Lancet, 399(10325), 629-655.
• Iskandar, K., Murugaiyan, J., Hammoudi Halat, D., Hage, S. E., Chibabhai, V.,
Adukkadukkam, S., ... & Van Dongen, M. (2022). Antibiotic discovery and
resistance: the chase and the race. Antibiotics, 11(2), 182.
• Centers for Disease Control and Prevention. (2019). Antibiotic resistance threats
in the United States, 2019. US Department of Health and Human Services,
Centres for Disease Control and Prevention.