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2020-04-22| In-DepthR&D

Is Antibiotic Resistance Here to Stay?

by Tulip Chakraborty
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T. Chakraborty, Ph.D.

Introduction

During the 1900s, infectious diseases were the leading cause of death. Thereafter, the discovery, commercialization, and routine administration of antimicrobial compounds have paved the way for radical changes in the therapeutic paradigm. Antibiotics play an extremely crucial role in the development of complex surgical procedures, organ transplantations, and cancer treatments, among others. Unfortunately, the gradual increase in resistance among various bacteria are now threatening successful outcomes and jeopardizing the lives of critically ill patients. The World Health Organization (WHO) recognizes antimicrobial resistance as one of the three most important public health threats of the 21st century [1].

The antibiotic resistance crisis is a result of antibiotics overuse and the shortage of initiatives by the pharma industry due to the strict regulatory requirements and economic constraints. As opposed to therapeutic drugs, antibiotics are cheaper and yield tiny margins for manufacturers. As a result, they go bankrupt or get acquired by more prominent firms. The Centers for Disease Control and Prevention reports that antibiotic-resistant organisms cause at least 23,000 annual deaths in the US [2]. Moreover, approximately 300 million deaths are estimated by 2050, with a loss of about $100 trillion to the global economy [3]. This situation is fueled further by the absence of a prospective antibiotic pipeline, resulting in the emergence of various new infectious diseases that have practically little to no antibiotics associated with them.

 

Mechanisms of Antibacterial Resistance

Bacterial genomes have incredible plasticity that allows them to react to xenobiotics, including antibiotics. Years of evolution have given bacteria the ability to acquire antimicrobial resistance by two primary means, spontaneous mutations, and horizontal gene transfer. When a bacterial population is exposed to antibiotics, the survivors pass on the acquired resistant mutations to future generations. Horizontal gene transfer, on the other hand, is a process when bacteria acquire antibiotic-resistant genes from foreign sources and incorporate it into their genome [4].

These alterations then lead to antimicrobial resistance through various mechanisms. Efflux pumps on the bacterial cell membrane can pump out a drug’s antibiotic compounds, to reduce its effect. Contrarily, it can also modify cell membrane constituents to inhibit drug permeability. By producing β-lactamase, they can inactivate antibiotics like penicillin by destroying their active site. Some others produce proteins that modify the antibiotics in a way that destroys its identification and the bactericidal properties [5].

Further, a few have also developed mechanisms to modify drug targets and bypass the effect of antibiotics. By adding chemical groups or producing alternative proteins to bind competitively to the antibiotic, they can reduce drug efficacy. For example, Staphylococcus aureus has been shown to harbor a resistance gene mecA that can produce a penicillin-binding protein. Once bound, it can deactivate the drug by blocking the active β-lactam ring. Besides, they can also reprogram the target to a different protein structure to bypass the drug altogether [6].

A bacterial cell can employ multiple mechanisms at one time to develop drug resistance. For example, the resistance to Fluoroquinolone is a cumulative effect of different biochemical mechanisms like i) mutation in the target site of the drug, ii) induction of efflux pumps to pump out the drug, and iii) protecting the target of the drug [4]. Moreover, the preference for choosing biochemical pathways to bypass is species dependant. Two different species can inactivate the same antibiotic in distinct ways. While Gram-negative bacteria produce β-lactamase, gram-positive bacteria resort to drug target modifications to achieve penicillin resistance [7].

With centuries of evolution, certain bacteria have developed resistance to multiple classes of antimicrobials [8]. These multiple drug resistant (MDR) bacteria can inhibit various categories of antibiotics by rapid mutations, pumping out the drug through efflux pumps, modifying the drug targets, and other mechanisms at tandem making it a huge risk factor to public health and safety [9].

 

Antibiotic Resistance Breakers (ARB’s)

Since 2000, some new classes of antibiotics have been launched. They include linezolid, daptomycin, retapamulin, and fidaxomicin. Unfortunately, they are effective only against gram-positive bacteria. However, all hope is not lost. Helperby Therapeutics, a British biopharma, has developed a solution by producing compounds called Antibiotic Resistance Breakers (ARBs). When combined with existing antibiotics, ARBs increase potency against both gram-positive and gram-negative bacteria.

ARBs are patented exclusively and have high value in commercial markets. One such combination was found to be active against three pathogens resistant to Carbapenem. They are Pseudomonas aeruginosa, Acinetobacter, and Carbapenem-resistant Enterobacteriaceae (CRE). These pathogens are dangerous and are responsible for the spread of septicemia and pneumonia. Helperby claims to be one of the six pharmaceutical companies in the world to have an ARB effective against all the three critical priority pathogens. Their products are anticipated to reach the market in the next 3-5 years.

 

Recent Advances in the Development of New Antibiotics

Dr. Anthony Fauci, the Director of the National Institute of Allergy and Infectious disease, predicted that the number of worldwide deaths in the world might increase by ten-fold by 2050, emphasizing the problems associated with antibiotic resistance [10]. Forty-one new antibiotics have been recently developed to treat serious bacterial disorders. Among them, Merck’s Recarbrio is of particular interest. The drug is a combination of three compounds and was FDA approved last July for the treatment of complicated urinary tract infections and other gram-negative bacterial infections [11]. Another noteworthy one is the experimental antibiotic, Darobactin, derived from bacteria living in nematodes. The drug shows activity against most gram-negative bacteria, both in vitro and in animal models [12]. If customized for human use, this antibiotic would be first to be developed from an animal microbiome.

 

Future Directions

With time, rapidly emerging antibiotic-resistant bacteria threaten the extraordinary health benefits that have been achieved by the antibiotics. This global crisis reflects the past follies of antibiotic abuse, which is further aggravated by a dry pipeline of new antibiotic agents in the pharmaceutical industry. Antibiotic-resistant infections are responsible for putting a substantial economic burden on the present health care system. Coordinated efforts from the pharma companies, government bodies are required to implement new policies, advance research efforts, and take active steps to manage this crisis.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: EXBLIFEP Surpasses Phase III, Presents Novel Solution for Antibiotic Resistance Crisis in Treating Complicated UTI

References
  1. http://www.who.int/drugresistance/documents/surveillancereport/en/
  2. http://www.cdc.gov/drugresistance/threat-report-2013/index.html
  3. http://amr-review.org/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888801/
  5. https://www.ncbi.nlm.nih.gov/pubmed/24678768
  6. https://www.reactgroup.org/toolbox/understand/antibiotic-resistance/resistance mechanisms-in-bacteria/
  7. Ramirez MS, Tolmasky ME. Aminoglycoside modifying enzymes. Drug Resist Updat. 2010 Dec;13(6):151–71.
  8. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-0691.2011.03570.x
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847397
  10. https://news.harvard.edu/gazette/story/2017/10/symposium-explores-the-science-and-business-of-reducing-resistance-to-drugs-to-prevent-a-post-antibiotic-age/
  11. https://www.mrknewsroom.com/news-release/prescription-medicine-news/fda-approves-mercks-recarbrio-imipenem-cilastatin-and-releba
  12. https://www.nature.com/articles/s41586-019-1791-1

 

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