drug discovery

Using machine learning to super-charge anti-infective drug discovery: the case of Halicin

Jon Otter (@jonotter) Antibiotic resistance , , , ,

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Yes, it’s true. There is more to HCAI & AMR (and this blog) than COVID-19! To prove it, I’m posting on something different today – the use of AI to streamline the anti-infective drug discovery process. Scientists at MIT have used machine learning (aka “deep learning”) to improve the drug discovery process, by predicting antimicrobial activity in molecules that are different from known antibiotics. This process has yielded Halicin, a promising candidate molecule for a broad-spectrum antimicrobial agent – which is, of course, a long way from clinical trials!

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Lugdunin: a storm in a nasal passage?

Jon Otter (@jonotter) Antibiotic resistance , ,

Nez_d'homme

It’s great to be able to report some much-need progress on the drug discovery front, with a Nature paper about a new antibacterial, lugdunin. Lugdunin is produced by S. lugdunensis and probably explains why this organism can out-compete S. aureus to colonise the nasal passages. Whilst the research has generated a great deal of positive press coverage – and so it should – but much like teixobactin, it will not go far to alleviate our problems with anti-infective-resistant bacteria.

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We need new antibiotics for Gram-negative, not Gram-positive bacteria

Jon Otter (@jonotter) Antibiotic resistance, CRE , ,

gram stain pos and neg

The threat from antibiotic resistance is more pink than purple. You probably need to be a microbiologist to get this: Gram-positive bacteria (such as MRSA and C. difficile) stain purple in the Gram stain, whereas Gram-negative bacteria (such as Klebsiella pneumoniae and Acinetobacter baumannii*) stain pink. All of the international concern surrounding antibiotic resistance from the WHO, CDC, PHE and others have focused our mind on one threat in particular: carbapenem-resistant Enterobacteriaceae (CRE). The Enterobacteriaceae family of bacteria are all Gram-negative, so we need to focus our drug discovery towards the Gram-negatives rather than the Gram-positives.

I blogged last week on the fanfare surrounding the discovery of Teixobactin. Whilst it looks promising, it’s still a long way from the pharmacy shelves, is most certainly not “resistance-proof” and, most importantly, only active against Gram-positive bacteria. I’ve received some useful comments in response to the blog pointing me in the direction of another novel antibiotic, Brilacidin.

Brilacidin is a novel antibiotic class that is in many ways more promising than Teixobactin, not least due to its activity against both Gram-positive and Gram-negative bacteria. Furthermore, it’s much closer to the pharmacy shelves, having undergone promising Phase 2b clinical trials (showing broadly comparable efficacy to daptomycin for the treatment of acute bacterial skin and skin structure infections).

Brilacidin is not without its problems though. Firstly, it is not active against A. baumannii. This is important, since multidrug-resistant – especially carbapenem-resistant – A. baumannii is a serious problem in ICUs around the world. Secondly, although the antibiotic is truly novel (working on the principle of ‘defensin-mimetics’), manufacturer claims that resistance is ‘unlikely’ are as fanciful as the “resistance-proof” claims associated with Teixobactin. Every class of antibiotics was novel once. And resistance has developed to them all!

There are some other emerging options for the antimicrobial therapy of multidrug-resistant Gram-negative bacteria. A number of beta-lactamase inhibitors combined with existing antibiotics are currently at various phases of the clinical trials process (for example, avibactam and MK-7655). Again though, although promising, beta-lactamase inhibitors have limitations, the most important being their specificity. For example, these inhibitors are effective against only some beta-lactamases (and have a blind spot for the metallo beta-lactamases such as NDM-1).

So, there is no silver bullet coming through the pipeline. And there will be no silver bullet. However clever we are in discovering or designing new antibiotics, some bacteria will always find a way to become resistant. It would be naive to think otherwise. Drug discovery is one part of our response to the rising threat of antibiotic resistance, but we ultimately need to focus on prevention over cure.

* Actually, A. baumannii is a bit “Gram-variable” so is somewhat pinky-purpley – but let’s not get too hung up on that. 

Image credit and caption: Marc Perkins. ‘Gram stain demonstration slide. A slide demonstrating the gram stain. On the slide are two species of bacteria, one of which is a gram positive coccus (Staphylococcus aureus, stained dark purple) and the other a gram-negative bacillus (Escherichia coli, stained pink). Seen at approximately 1,000x magnification.’

Teixobactin: a “resistance proof” antibiotic? No chance!

Jon Otter (@jonotter) Antibiotic resistance , , ,

It’s not often that I feature a mighty Nature paper on this ‘lil old blog, but this is a big one. A team from Northeastern University in Boston and a small company called NovoBiotic Pharmaceuticals have discovered a truly novel antibiotic, called ‘teixobactin’.

The finding stems from the fact that 99% of microbes in the external environment cannot be cultured in the laboratory. In order to overcome this problem, the authors ingeniously brought the laboratory to the soil by using the iChip (pictured below). The iChip is a way of capturing the growth of a microbe in its natural environment. Curiously, once grown in the iChip, most of the colonies could then be sub-cultured in the laboratory. When using the iChip, around 50% of the microbes in the soil can be cultured (compared with 1% using conventional methods).

ichip

The authors then screened extracts from an awful lot of isolates (10,000) for antimicrobial activity, and found one that stood out: ‘teixobactin’. It’s a novel cell wall inhibitor that interrupts peptidoglycan synthesis not by targeting proteins (such as the enzymes targeted by β-lactams), but by targeting lipids.

Teixobactin has impressive activity against a range of Gram-positive pathogens of importance to healthcare including S. aureus, E. faecium / faecalis, various streptococci, M. tuberculosis and, importantly, C. difficile. The authors found that teixobactin had equivalent activity to oxacillin (methicillin) in vitro, and superior activity to vancomycin both in vitro and in an animal model.

However, there are some problems:

  • Firstly, and most importantly, there is no activity against Gram-negative bacteria. Since the source microbe, the newly described Elftheria terrae, is a Gram-negative bacterium, this is no surprise, otherwise it would inhibit itself in the soil!
  • Secondly, the antibiotic is still a long way from the clinic, and has to undergo a series of rigorous human clinical trials before reaching the pharmacy shelves.
  • Thirdly, the authors made the promising discovery that they did not identify reduced susceptibility to teixobactin despite serial passage to sub-inhibitory doses for 27 days. The press have had a field day with this, and are talking in terms of “resistance resistant” antibiotics. But this is too much: the authors parallel the potential for resistance to teixobactin with the potential for resistance to vancomycin – and we are increasingly seeing clinically meaningful reduced susceptibility to vancomycin. There’s a rather obscure and quite frightening study showing that vancomycin resistance could be just around the corner: the study found that S. aureus exposed to sub-lethal doses of chlorhexidine as a surface biofilm became resistant to vancomycin after 48 hours (MIC >128 mg/L). So, bacteria will become resistant to whatever we throw at them, to a lesser or greater degree, given time and sub-lethal exposure.

So, teixobactin represents and exciting and huge leap forward in the process of antibiotic drug discovery – and we can expect more novel antibiotics to follow. However, we’d be foolish to think that resistance to teixobactin will not emerge in time.

Citation: Ling LL, Schneider T, Peoples AJ et al. A new antibiotic kills pathogens without detectable resistance. Nature 2015.

Image: NBC news.