Tackling Superbugs using Antibiotic Resistance Breakers
Antibiotics were discovered, more than 70 years ago with the purpose to treat life-threatening infections. However, unregulated prescribing and over-use of antibiotics have created a grim, and urgent situation. This requires a prompt need to innovate and build effective solutions against drug-resistant pathogens.
This write-up will discuss an oft-less-discussed approach to tackle bacterial resistance through Antibiotic Resistant Breakers.
What are Antibiotic Resistance Breakers?
Antibiotic resistance breakers (ARBs) are drugs that can be co-administered with the current class of antibiotics. Antibiotic Resistance Breakers were previously referred to as antibiotic adjuvants. Although ARBs may or may not have any direct antibacterial effect on the infecting bacteria, but they successfully show synergistic or additive effects in combating bacterial resistance.
The use of ARBs can help sensitize microbes to existing antimicrobials and prolong their usage. ARB is a broad term for various classes of chemicals. The mechanism by which they aid antimicrobials may be varied.
Why are Antibiotic Resistance Breakers “need of the hour”?
The first resistance was observed in staphylococci and streptococci after penicillin emerged as a commercial antibiotic in 1941. However, reports suggest an early warning was released about E.coli capable of inactivating penicillin in 1940 itself. The continuous natural evolution and changes in the cell physiology of bacteria have challenged the effectiveness of antibiotics [1].
According to the reports of WHO, 700,000 deaths were reported due to Antimicrobial resistance (AMR). In the times when more than 20 million deaths are estimated by 2050 by antimicrobial resistance, ARBs can turn the tables [2]. Innovations to develop new ARBs can be catalyzed by prioritizing research aimed at understanding different cellular and/or molecular changes bacteria undergo that provide them with antimicrobial abilities.
Bacteria typically develop resistance to antimicrobials by certain broad strategies. The first is preventing any antimicrobial compound from entering the microbial cell. This is achieved by changing membrane permeability and antibiotic influx.
The second strategy employed by microbes is altering the target site of its own enzymes that the antibiotic binds to. The most aggressive strategy, however, is production of enzymes that cleave the antibiotic.
The mechanisms of Antibiotic Resistance Breakers
ARBs in turn target these cellular defense mechanisms, making the co-administered antimicrobial agent effective again. ARBs can be classified into three broad categories.
- Enzyme Inhibitor Modifiers-
Examples of this are β lactamase inhibitors like co-amoxiclav, co-ticarcillin, sulbactam, tazobactam, and Aminoglycoside modifying enzymes like Gentamicin and Amikacin.
2. Membrane Permeabilizers-
Examples of this are Polymyxins (Polymyxins B & E), other Polymyxin derivatives and Plant-derived phenolic compounds.
3. Efflux Pump Inhibitors PAβN (Phenylalanine-Arginine-β-Naphtylamide), NMP, and Arylpiperazines are some examples of efflux pump inhibitors [3].
Worldwide efforts to deal with AMR through ARBs
Funding platforms such as CARB-X and EU-backed Innovative Medicines Initiatives support the research and innovations for the organizations working on solutions for Antimicrobial Resistance.
To deal with the superbugs fast track designing of early diagnosis and effective therapeutic treatment is required. As per a report published in the American Chemical Society, researchers claim Fabimycin has successfully worked to overcome drug resistance of gram-negative bacteria in lab experiments. This can be a noteworthy solution to treat pneumonia, urinary tract infection and blood diseases [4].
EU-funded QureTech’s project focuses on new chemical entities, referred to as GmPcides to restore antibiotic susceptibility [5]. This could serve as a breakthrough treatment for gram-positive bacterial resistance. It can be helpful to treat major respiratory, abdominal and other infections and will deal with Vancomycin and Methicillin resistance against Enterococci and Staphylococcus respectively.
PK150, an antibiotic discovered by the team of Stephan Sieber at the Technical University of Munich, Germany is capable to disarm bacterial resistance [6]. It is a useful weapon against multi-drug-resistant Staphylococcus aureus by targeting bacterial energy metabolism.
Various Bengaluru and Pune-based startups supported by C-CAMP are working to innovate and prevent infections in healthcare facilities. Research on ‘Catheters resistance to biofilm infections’ by Dr. Prashant Rathinam is one such effort [7].
Conclusion:
As the pace of development of new antibiotics slows significantly the need to prolong the clinical viability of our existing antibiotics becomes urgent. Push to develop new ARBs, testing moon-lighting functions of other chemical entities, researching novel delivery mechanism like using nano-carriers, nanoparticles may become the future backbone to break AMR.
Disclaimer: The blog is a compilation of information on a given topic that is drawn from credible sources; however, this does not claim to be an exhaustive document on the subject. The mention of entities, networks, consortiums, or partnerships is merely to highlight the stakeholders working in the field and does not reflect attestations, validations or promotion of their work. It is not intended to be prescriptive, nor does it represent the opinion of C-CAMP or its partners. The blog is intended to encourage discussion on an important topic that may be of interest to the larger community and stakeholders in associated domains.
Sources:-
3) https://www.mdpi.com/2079-6382/12/1/180
4) https://pubs.acs.org/doi/10.1021/acscentsci.2c00598
