Antibiotiocs for all microbial infestation?

 The confluence of the ascendancy of empiric treatment, the urge for self-medication, the reluctance of lab testing based on affordability, and the overlapping symptoms of the plethora of microbial infections have led to over-dependency on antibiotics and consecutively, their overuse. In its September 2022 article, WHO disclosed the death of 12.7 Million Worldwide due to bacterial Antimicrobial Resistance (AMR) catering to the injudicious use of antibiotics. The evolution of bacterial cells to develop resistance is a natural phenomenon, however, one of the accelerating factors is the improper use of antibiotics. More alarmingly, the development of new antimicrobials is slow.

The injudicious use of antibiotics is an umbrella word for the probable event of using an antibiotic even when not required, for example, taking antibiotics in case of a viral or a protozoal disease or not completing the due medicine course, this in its entirety leads to SuperBugs. Sounding fictitious tied to reality, SuperBugs are microbes resistant to multiple antimicrobial drugs, manifested mainly in bacteria. The more antimicrobial exposure, the elevated the chances of SuperBugs.

 

Antimicrobial resistance is posing a grave threat to mankind as the concept of modern medicine is dependent on the use of antimicrobials to prevent infection- from chemotherapy to surgeries. Overuse of antimicrobial drugs is also causing resistance against them in significant microbes thus rendering the drugs ineffective and resulting in untreatable infections. The mechanisms the microbes use to hinder the effect of antimicrobial drugs are called resistance mechanisms. These could be - restricting the designated pathway of the antibiotic, pumping out the antimicrobial drugs from their cellular interior to the exterior by using transporter proteins called efflux pumps, changing the conformation of the drug, and bypassing its effects. Superbugs, on the other hand, being the most notorious of all, use distinct mechanisms to tackle the working of antibiotics.

 

In the case of Methicillin-Resistant Staphylococcus aureus (MRSA) which is a major superbug, the methicillin resistance has occurred because of the mutation of a penicillin-binding protein (PBP)- a chromosome encoded protein (Abdul H. Siddiqui et.al). Methicillin, a beta-lactam antibiotic, is a derivative of penicillin that actually binds to the penicillin-binding proteins of harmful Staphylococcus strains and inhibits transpeptidation, thus weakening cell walls and causing cell death. The MRSA strain is capable of expressing an additional PBP (PBP2a) that essentially resists the action of the antibiotic but can easily carry out the transpeptidation reactions (Paul B. Stapleton, Peter W. Taylor) and causes pneumonia and sepsis.

Several strains of Enterococci have become immune to commonly used antibiotics either because of their intrinsic resistance or the use of foreign genetic material through plasmids and transposons. As of now, there are 5 identified strains of Enterococcus spp. that are vancomycin-resistant- Van A, Van B, Van C, Van D, and Van E. Among these, the Van A strain is the most dangerous, and the best evidence of vancomycin resistance is found in the van A gene cluster transposon, Tn1546. During normal peptidoglycan synthesis in Enterococci, two molecules of D- alanine is joined by a ligase enzyme to form D- Ala - D-Ala, and UDP-N-acetylmuramyl tripeptide is converted to UDP-N-acetylmuramyl pentapeptide. Vancomycin binds with high affinity to the D- Ala - D- Ala termini and stops the conversion to UDP- N- acetylmuramyl pentapeptide. In the case of the resistant strain, Van A protein is of an altered specificity that forms D-Ala - D-Lac instead of D-Ala - D-Ala and inhibits Vancomycin binding by lowering its affinity levels (Yesim Setinkaya et.al).

 

The effectiveness of antimicrobial drugs in treating cystic fibrosis caused due to Pseudomonas aeruginosa is decreasing daily as the strains become stronger and more resistant. When colistin was used as a last line of defense by cystic fibrosis clinicians in Denmark, clinical isolates of Pseudomonas aeruginosa from chronically treated cystic fibrosis patients showed hypermutations in some of its subpopulations, hinting that there might be heteroresistant activity by the bacterial cells. Colistin contains polymyxin that binds to the lipid polysaccharide of the outer membrane, causes membrane permeabilization, and inserts itself into the inner membrane. This inhibits cellular respiration and cell death occurs. The mutant strains were observed to have gain-of-function pmrB alleles that granted polymyxin resistance. The novel pmrB alleles add a 4- amino L- arabinose to the lipid A part of the lipid polysaccharide and modify it, resulting in augmented polymyxin resistance (Samuel M. Moskowitz et.al)

 

Summarising the point that was intended to be laid forward by these examples - Antibiotics are losing their efficiency against SuperBug bacteria that is solely due to incautious use of the same. Overuse of antibiotics means elevated exposure of bacteria to the concerned drug thereby facilitating a plethora of mutations aimed at self-protection. One of the major reasons why AMR needs to be avoided is that Multi-Drug Resistance mechanisms can be turned from an epidemic into a pandemic, thereby bringing in clinical and financial burdens worldwide. Till the time the rate of evolution in bacteria is more rapid than our rate of developing new effective drugs, informed and prudent use of antibiotics is at present, the only preventive measure. The rational use of antibiotics will slow down the evolution rate of bacterial cells, allowing scientists and researchers to develop stronger and more effective drugs.


Authors : Sruty Dey, Heeya Gupta

 

References -

1.Bendala Estrada, A.D., Calderón Parra, J., Fernández Carracedo, E. et al. Inadequate use of antibiotics in the covid-19 era: effectiveness of antibiotic therapy. BMC Infect Dis 21, 1144 (2021). https://doi.org/10.1186/s12879-021-06821-1

2. Ventola C. L. (2015). The antibiotic resistance crisis: part 1: causes and threats. P & T : a peer-reviewed journal for formulary management, 40(4), 277–283.

3.Prestinaci, F., Pezzotti, P., & Pantosti, A. (2015). Antimicrobial resistance: a global multifaceted phenomenon. Pathogens and global health, 109(7), 309–318. https://doi.org/10.1179/2047773215Y.0000000030

4..Davies, J., & Davies, D. (2010). Origins and evolution of antibiotic resistance. Microbiology and molecular biology reviews : MMBR, 74(3), 417–433. https://doi.org/10.1128/MMBR.00016-10

5. Stapleton, P. D., & Taylor, P. W. (2002). Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. Science progress, 85(Pt 1), 57–72. https://doi.org/10.3184/003685002783238870

6.Cetinkaya, Y., Falk, P., & Mayhall, C. G. (2000). Vancomycin-resistant enterococci. Clinical microbiology reviews, 13(4), 686–707. https://doi.org/10.1128/CMR.13.4.686

7.Common drug-resistant superbug develops fast resistance to ‘last resort’ antibiotic | University of Oxford

8. Moskowitz, S. M., Brannon, M. K., Dasgupta, N., Pier, M., Sgambati, N., Miller, A. K., Selgrade, S. E., Miller, S. I., Denton, M., Conway, S. P., Johansen, H. K., & Høiby, N. (2012). PmrB mutations promote polymyxin resistance of Pseudomonas aeruginosa isolated from colistin-treated cystic fibrosis patients. Antimicrobial agents and chemotherapy, 56(2), 1019–1030. https://doi.org/10.1128/AAC.05829-11

9.Keith P. Romano, Thulasi Warrier, Bradley E. Poulsen, Phuong H. Nguyen, Alexander R. Loftis, Azin Saebi, Bradley L. Pentelute, Deborah T. Hung. (2019).

Mutations in pmrB Confer Cross-Resistance between the LptD Inhibitor POL7080 and Colistin in Pseudomonas aeruginosa. https://doi.org/10.1128/AAC.00511-19

 

 

 

 

                      

                     

 

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