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Mitchell Crawford

Lydia Mullins

Viable Techniques to Combat Antibiotic Resistance

For generations, bacteria have imposed a major threat to the health and prosperity of

humanity. This constant threat of illness due to bacteria has influenced the creation of incredible

inventions to help fight bacteria: thienamycin, penicillin, and modern antibiotics. However,

though heavy exposure to antibiotics helps to eliminate a large portion of the bacterial

population, a community of bacteria that develops resistance to the treatment survives and

reproduces. This resistance-inducing allele has a very high probability to fixate within a

population because the trait is highly favorable/fit to negate drug effectiveness. One of the

factors leading to this rise in antibiotic resistant bacteria, also known as Superbugs, is through

the overuse and misuse of these medications, as well as the lack of new drug development in the

pharmaceutical industry (Ventola 2015). The creation of antibiotics has paved the way to

unprecedented medical and societal developments in today’s health system. Without antibiotics,

such achievements in modern medicine, such as organ transplantation, cancer chemotherapy, and

treatment of preterm babies would not be successful (Laxminaravan 2013). Within just a few

years, we could be faced with dire setbacks, medically, socially, and economically, unless real

global coordinated action is taken immediately to combat this rise in antibiotic resistance

bacteria (Laxminaravan 2013). Potent procedures that are being developed to help combat drug-

resistance include modifying current antibiotics by adding inhibitors, using Outer-membrane

permeability and polymyxins, incorporating nanoparticle-based antibacterial agents, and by

using combination antibacterial agents.

Bacteria can gain resistance in a variety of ways. By attaching to a surface and growing

as a biofilm, bacteria can gain resistance over the beta-lactams antibiotics through the production

of hydrolytic enzymes termed beta-lactamases (Stewart 2002). These biofilms form persister

cells that allow the bacteria to survive through slow growth, adaptive stress hormones, and

nutrient limitation. Some bacteria that arises from this include: Staphylococcus epidermis and

Pseudomonas Aeruginosa (Stewart 2002). The department of Health in London has found that

100,000 to 200,000 tons of antibiotics are used in the agriculture and veterinary sectors (Howard

2013). These antibiotics will eventually be ingested by humans and once the antibiotics are in

our system, they begin to develop resistance (Howard 2013). Not only does the direct

consumption of the antibiotics in animals affect development of antibiotic resistance, but the

waste of animals and humans play a big role in resistance as well. Animal and human waste are a

major transport vessel for antibiotic resistant organisms and once the waste is released into

water, the antibiotic resistant bacteria can spread their genes into water microbes (Baquero

2008). These water microbes can make their way into the soil that plants get their nutrients from,

and then begin to develop antibiotic resistance in the nutrients that the plant uptakes. In order to

slow this spread of antibiotic resistance, researchers must look at different ways to modify

current antibiotics to terminate antibiotic resistance.

The most conventional method of treating these resistant bacterial colonies is to simply

upgrade currently used models or release more potent antibiotics. Although some bacteria have

the potential to become up to 4 times more resistant to antibiotics after prior exposure (Huang

2015), the main theme behind the use of antibiotics today is their longevity. Any new antibiotic
agent should be unlikely to induce resistance in a bacterial colony, and should show a relatively

low selectivity. There are two classifications of antibiotics: bacteriostatic, which slow down the

bacteria growth to the point where natural immune responses can eliminate the bacteria colony,

and bactericidal, that directly attack and terminate the bacteria colony (Ventola 2015). Dr.

Wright and his lab team reported on 2 different types of bacteriostatic antibiotics that are being

used to combat superbugs through the development of inhibitors on resistance mechanisms:

Beta-Lactams and Aminoglycosides (Wright 2000).

Clavulanic acids, such as sulbactam and tazobactam, are working nonmetallo beta-

lactamases inhibitors that have been clinically used for up to 15 years in the treatment of both

gram-negative (e.g. Escherichia coli) and gram-positive (e.g. Staphylococcus aureus) bacteria

(Wright 2000). Resistance to the aminoglycoside antibiotics occurs primarily thorough the

region-specific chemical modification catalyzed by O-phorphoryltransferases, N-

acetyltransferases, and O-adenyltranferases (Wright 2000). Due to the broad dissemination of

these resistance mechanisms in pathogenic bacteria, use of aminoglycoside antibiotics, such as

kanamycin, has been reduced. Dr. Wright found that the most useful micromolar inhibitor was

the aminoglycoside adenyltransferase of ANT (2”) found in gram-negative pathogens. This

inhibitor reversed tobramycin and dibekacin in E. coli by harboring the ANT (2”) gene that

builds antibiotic resistance in the gram-negative pathogens (Wright 2000).

One of the leading causes of bacterial infections is that there is intrinsic antibiotic

resistance with regards to outer-membrane permeability. Georgina Cox, a researcher at the

DeGroote Institute for Infectious Disease research, found that gram-negative bacteria, such as

Klebsiella and Acinetobacter, can permeate through the bilayer because there is a low

permeability for gram-positive bacteria, but high permeability for gram-negative bacteria (Cox
2013). This phenomenon has lead researchers like Tony Velkov to look for solutions to

preventing gram-negative bacteria from permeating into the cell. One solution that Velkov found

was the use of polymyxins. Polymyxins are natural product lipopeptide secondary metabolites

produced by the gram-positive soil microbe Paenibacillus polymyxa (Velkov 2016). This idea

was developed by the BioSource Pharmaceuticals group, and their strategy involved removing

N-terminal fatty acyl groups of polymyxin B. By taking out the N-terminal fatty acyl groups,

they reduced the hydrophobicity of N-terminal fatty acyl groups that were identified to be a “hot-

spot” for nephrotoxicity found in antibiotics (Velkov 2016). The lead compound to emerge from

this study was the N-terminal 2-chlorophenylurea derivative CB-182,804. This compound had a

high target against gram-negative bacteria and showed efficacy to reduce nephrotoxicity in

resistance (Velkov 2016). Polymyxins can help resolve the problem presented by Georgina Cox

of gram-negative bacteria having a high-permeability through the bilayer. By targeting the

nephrotoxicity in gram-negative bacteria, the permeability of the gram-negative bacteria can be

eliminated by making them more hydrophobic (Velkov 2016), thus making them less likely to

permeate through the bilayer and cause infection.

When adding inhibitors to an antibiotic and changing the chemical build of a certain

antibiotic don’t prove to be effective, scientists must develop new and effective antibacterial

agents. There are a wide range of applications for antibacterial agents, but Dr. Xiaoquang Huang

has investigated the new idea of synthesizing a synergistic nanocomposite to the surface of

Selenium Nanoparticles, or otherwise known as “SeNPs”. The most common nanocomposite is

quercetin (Qu) and acetylcholine (Ach) and these nanocomposites have been reported to exhibit

a wide range of biological activities related to their antibacterial activity (Huang 2015). quercetin

has been reported to exhibit a wide range of biological activities related to their antibacterial
activity to combine to the receptor of a bacterial cell with the use of acetylcholine as a

neurotransmitter, and render the bacteria ineffective (Huang 2015). The properties of quercetin

and acetylcholine lead Huang’s team to synthesize quercetin and acetylcholine to combat

multidrug-resistant superbugs. Huang’s study found that nanocomposites of quercetin and

acetylcholine synthesized on the surface of selenium nanoparticles, Qu-Ach@SeNPs, are

effective against multidrug-resistant superbugs (MDRs) such as Methicillin-resistant

Staphylococcus aureus (MRSA) which are gram-positive bacteria (Huang 2015). Qu-

Ach@SeNPs is an example of a bactericidal antibiotic, because it attaches to the bacterial cell

wall, causing irreversible damage to the membrane and thus inhibiting the MRSA from causing

an infection. The success of Qu-Ach@SeNPs comprises a new class of inorganic nano-

antibacterial agents that can be used as useful applications in biomedical devices (Huang 2015).

Rather than improving and modifying a single antibiotic, Larry Badour, who conducts

research for the American Thoracic Society, has found that combination antibiotic therapy is an

effective strategy to combating antibiotic resistance. Combination antibiotic therapy deals with

the synergy of two antibiotics, and Badour and his team put this to test to see if it could help

reduce mortality for severe bacteremic pneumococcal pneumonia. The most common

combination therapies prescribed were beta-lactam/macrolide, vancomycin/beta-lactam, and

beta-lactam/aminoglycoside (Badour 2004). Compared to the patients treated with monotherapy

(only one antibiotic), the patients treated with combination antibiotic therapy saw a survival

increase by over 9 days (Badour 2004). The original mortality rate for an individual suffering

with Streptococcus pneumoniae went from a 14-day mortality to 23.5 days. In comparison to

monotherapy regimes, combination therapy increased survival twofold in critically ill patients
(Badour 2004). Combination antibiotic therapy is currently being researched to help eliminate

bacterial infections such as in vitro and other severe cases of pneumonia.

High exposure to antibiotics can eliminate a large portion of the bacterial population.

However, a community that is resistant to the treatment through various mechanisms survives.

Doctors are consistently over-prescribing medications to patients and this gives bacterial

populations more opportunities to develop resistance. The traditional response to antibiotic

resistance will be to update or create new antibiotics, yet natural selection will invariably select

for higher fitness phenotypes. For more permanent solutions, more research must be put into

exploring unconventional treatment options, such as the removal of N-terminal fatty acyl groups

to decrease permeability of gram-negative bacteria, the use of nanoparticle technology to cause

irreversible damage to the antibiotic-resistant bacteria, and the use of antibiotic combination

therapy to increase survivability in some cases of severe illnesses. All of these techniques are

relatively new, but have incredible specificity and effectiveness when it comes to removing

harmful bacteria. The harm caused to neighboring, beneficiary bacteria needs to be evaluated

within multiple environments to understand effectiveness. Over-prescription is a prominent

weakness, and changing public policy to educate the pharmaceutical industry to decrease

development of antibiotic resistance could prove beneficial. Bacteria is constantly evolving

resistance to modern medicine, and in order to combat this resistance scientists must research

new techniques to combat this resistance. Methods of nanoparticle technology, antibiotic

inhibitors, changing permeability of bacteria, and combination therapy are all effective

techniques for combating antibiotic resistance. However, bacteria can develop resistance in many

different ways for these techniques, so more research and more techniques of combating

antibiotic resistance must be sought after.

Works Cited

1. Wright, G., et al. (2000). Resisting Resistance: New Chemical Strategies for Battling
Superbugs. NeuroImage, Academic Press. 7(6). R127-R132

2. Stewart, P. S., et al (2002). Mechanisms of antibiotic resistance in bacterial biofilms.

International Journal of Medical Microbiology. 292(2) R107-113

3. Velkov, T., et al. (2016). Polymyxins: A new hope in combating Gram-negative

superbugs? Future Medicinal Chemistry. 8(10), R1017-1025

4. Laxminaravan, R., et al. (2013). Antibiotic Resistance-the Need for Global Solutions. The
Lancet Infectious Diseases Commission. 13(12) R1057-1098

5. Cox, G., et al. (2013). Intrinsic antibiotic resistance: Mechanisms, origins, challenges and
solutions. International Journal of Medical Microbiology. 303(6-7) R287-292

6. Ventola, C. L., et al. (2015). The Antibiotic Resistance Crisis. U.S. National Library of
Medicine. 40(4) R277-283

7. Howard, S. J., et al. (2013). Antibiotic resistance: Global response needed. Lancelet
Infectious Diseases Commission. 13(12) R1001-1003

8. Huang, X., et al. (2015). Investigation of functional selenium nanoparticles as potent

antimicrobial agents against superbugs. Acta Biomaterialia. 30(15) R397-407

9. Baquero, F., et al. (2008). Antibiotics and antibiotic resistance in water environments.
Current Opinion in Biotechnology. 19(3) R260-265

10. Badour, L. (2004). Combination Antibiotic Therapy Lowers Mortality among Severely Ill
Patients with Pneumococcal Bacteremia. American Journal of Respiratory and Critical
Care Medicine. 170(4)