New approaches to antibiotic resistance: Antibiotic adjuvants

27 Jan 2017
Written by
Dr Derry K Mercer
The bacteria in the culture on the left are sensitive to the antibiotics contained in the white paper discs. The bacteria on the right are resistant to most of the antibiotics.

Derry is 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. 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.

Resistance breakers

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). There are more in the pipeline, such as Carbavance® (meropenem/vaborbactam).

There are four potential classes of antibiotic adjuvant:

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

Resistance breakers (or 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 can lead to considerable cost savings by eliminating 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, which can sensitise resistant bacteria to the antibiotic minocycline.

R&D aproaches

Antibiotic adjuvants are the focus of Research & Development programs at biotechnology and pharmaceutical companies.

  • Spero Therapeutics' Potentiator program focuses on developing NCE ‘potentiators’ that specifically interact with the outer the membrane of Gram-negative bacteria to increase the membrane’s permeability. This allows antibiotics normally only effective against Gram-positive bacteria to enter Gram-negative bacteria and kill them, overcoming the intrinsic resistance of Gram-negative bacteria to these antibiotics.
  • Discuva Ltd's SATIN technology identifies the molecular target(s) of bactericidal hits and associated resistance genes at the same time. This enables the prioritisation of hits for optimisation that will ultimately have the best chance of clinical success.
  • NovaBiotics’ Nylexa™ is a novel broad spectrum antibiotic potentiator in development to be co-administered with a range of of antibiotic classes (including aminoglycosides, folate inhibitors and fluoroquinolones) against drug resistant, multiple-drug resistant and extensively-drug resistant Gram-negative and Gram-positive bacteria.

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.

 

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.

A version of this article also appears in the Biochemical Society blog.

Image credit: Dr Graham Beards at en.wikipedia