By Derry K Mercer, Principal Scientist at Novabiotics Ltd & member of the Biochemical Society Policy Advisory Panel

From cradle to grave, antimicrobials have become pivotal in safeguarding the overall health of human societies. According to the World Health Organization (WHO), antimicrobial resistance (AMR) is one of the biggest threats to global health today. Recently, at the United Nations, World Heads of State committed to taking a broad, coordinated approach to address the root causes of AMR across multiple sectors, especially human health, animal health and agriculture, only the fourth time that a health issue has been taken up by the UN General Assembly. According to the O’Neill report, it is estimated that 700,000 people die annually from drug resistant infections. In the US alone, more than two million infections a year are caused by bacteria resistant to at least one antibiotic, costing the US health system more than US$20 billion in excess costs annually.

While research and development into new antimicrobials remains a vitally important pursuit for combatting the problem of resistance, alternative approaches to the burgeoning problem of antibiotic resistance are also urgently needed. Such methods include reducing inappropriate and unnecessary antibiotic use, decreasing the use of antimicrobials in agriculture, improved hygiene and sanitation, vaccine development, global public awareness and surveillance programmes and development of rapid diagnostics.

One approach that has received less attention than is perhaps warranted is the use of antibiotic adjuvants, also referred to as resistance breakers and antibiotic potentiators. These are non-antibiotic compounds that, when co-administered with antibiotics, act to block resistance or enhance antimicrobial activity. One class of antibiotic adjuvant, used successfully in the clinic for almost 30 years, are β-lactamase inhibitors. These act by blocking the activity of β-lactamases, enzymes that break down β-lactam antibiotics and cause resistance to probably the most widely used class of antibiotic in our current armamentarium. Existing β-lactam/β-lactamase inhibitor combinations include Tazocin^® (piperacillin/tazobactam) and others have recently been approved for clinical use, such as Avycaz^® (ceftazidime/avibactam). In addition, more are in the pipeline such as Carbavance^® (meropenem/vaborbactam).

There are four potential classes of antibiotic adjuvant;

1. anti-resistance drugs designed to increase the effects of current antimicrobials (potentiators)
2. anti-virulence drugs directed against microbial virulence factors
3. those that enhance the ability of the host to combat infection
4. alternative therapies such as bacteriophage therapy, probiotics and oral rehydration for diarrhoeal disease.

Resistance breakers/antibiotic adjuvants may be new chemical entities (NCEs) or a repurposed existing drug. One advantage of using a repurposed drug is that these drugs have known toxicology and pharmacology profiles and therefore there can be considerable cost savings as a result of elimination of much of the toxicological and pharmacokinetic assessment that would normally be required for approval of a new drug. An example of a potential repurposed anti-resistance drug is the anti-diarrhoeal loperamide that can sensitize resistant Gram negative bacteria to the antibiotic minocycline.

An example of type 1. adjuvants include the synthetic α-hydroxytropolones. Bacterial aminoglycoside-2″-O-nucleotidyltransferases adenylate aminoglycoside antibiotics (eg tobramycin) creating aminoglycoside resistant bacteria. Inhibition of these enzymes by synthetic α-hydroxytropolones would therefore restore the activity of these drugs in resistant bacteria.

Antibiotic adjuvants, other than β-lactamase inhibitors, are the focus of Research & Development programs at biotechnology and pharmaceutical companies. For example, Spero Therapeutics Potentiator program focuses on developing NCEs ‘potentiators’ that specifically interact with the outer membrane of Gram-negative bacteria to increase the membrane’s permeability, thus allowing antibiotics normally only efficacious against Gram-positive bacteria to enter Gram negative bacteria and kill them, thus overcoming the intrinsic resistance of Gram negative bacteria to these antibiotics. A related approach has been adopted by Discuva Ltd, in which their SATI^N technology identifies the molecular target(s) of bactericidal hits and associated resistance genes at the same time, thereby enabling the prioritisation of hits for optimisation which will ultimately have the best chance of clinical success. Finally, NovaBiotics’ Nylexa™ is a novel broad spectrum antibiotic potentiator in  development as an adjunct to be co-administered with a range of of antibiotic classes (including aminoglycosides, folate inhibitors and fluoroquinolones) against drug resistant, MDR and XDR Gram negative and Gram positive bacteria.

Antibiotic sensitivity and resistance. Credit: Dr Graham Beards at en.wikipedia [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)%5D, via Wikimedia Commons.

It is important that when considering approaches to reduce the problems associated with antimicrobial resistance, all possible avenues are considered and investigated, as some of the less obvious approaches may turn out to be sources of success in the future.

The Biochemical Society, http://www.biochemistry.org, works to promote the molecular biosciences; facilitating the sharing of expertise, supporting the advancement of biochemistry and molecular biology and raising awareness of their importance in addressing societal grand challenges. We achieve our mission by bringing together molecular bioscientists, supporting the next generation of biochemists, promoting and sharing knowledge, and promoting the importance of our discipline.

NovaBiotics Ltd is a leading clinical-stage biotechnology company focused on the design and development of first-in-class anti-infectives for difficult-to-treat, medically unmet diseases. The Company’s advanced portfolio of antimicrobial therapeutic candidates targets large and important markets with significant unmet clinical needs, including Lynovex^®, an orphan drug candidate for cystic fibrosis, Novexatin^®, a potential step change therapy for onychomycosis and Novamycin^®, a novel antifungal peptide in development for the treatment of aspergillosis, candidiasis and cryptococcosis.