Seminar report | How to make resistance-proof antibiotics (LSHTM, 16 November 2017 – Dr Luiz Pedro Carvalho)

One of the big challenges for tackling antimicrobial resistance is the lack of new antibiotics in the development pipeline. When investigating or selecting new compounds to take forward into pre-clinical and clinical development, it will be important to select drugs that are likely to have a long shelf life – i.e. ones that will delay the development of resistance for as long as possible. Such compounds will provide longer-lasting solutions and will be more attractive to drug developers as the potential for recoupling research and development costs will be greater if the drug is marketable for a long time.

This is where the work of Dr Luiz Pedro Carvalho from the Francis Crick Institute and colleagues from LSHTM comes in. At this seminar, Dr Carvalho presented recent work that aims to address the question of ‘How can we make resistance-proof antibiotics?’

The presentation focussed on the situation with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). TB is a global public health problem and the figures present a stark picture. According to CDC and the 2017 Global tuberculosis report from WHO, around one third of the world’s population is infected and in 2016 there were 1.7 million deaths from TB. Drug resistance is a major problem: ~490,000 of new cases in 2016 were resistant to multiple antibiotics (multidrug-resistant TB; MDR-TB), and extensively drug-resistant TB (XDR-TB) is almost untreatable. Thus the focus of the research community is now on dealing with the problem of drug-resistant TB.

D-cycloserine is a drug used as second-line treatment of MDR-TB and XDR-TB. Resistance against the drug is not yet widespread. Given that resistance against this compound is rare, Dr Carvalho and colleagues have used D-cycloserine as a model to understand which characteristics antibiotics need to have in order to prevent resistance from developing.

Sequencing by Dr Teresa Cortes (LSHTM) identified 11 strains with mutations that confer resistance to D-cycloserine. Now these two groups are trying to understand what are the molecular and cellular basis for resistance to D-cycloserine and why these mutations are not present in M. tuberculosis strains infecting humans.

So what does this mean for drug development? This work suggests that in taking a compound through the development pipeline, researchers should focus on identifying candidates that we know (or suspect) will have an ultra-low mutation rate. Easier said than done, perhaps. Compounds that target more than one process is one way to address this.

A manuscript describing this work is currently in preparation, so look out for further details to follow in the published articles.

Written by Dr Sarah Woodhall (AMR Centre Student Liaison Officer)

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