Imitation of beta-lactam binding enables broad-spectrum metallo-beta-lactamase inhibitors by Brem et al., (2022)
This international collaboration led to the identification of indole-2-carboxylates as a novel metallo-beta-lactamase inhibitor warhead that mimics the enzyme-substrate complex.
InC58
I’m fortunate to have reviewed many hit-, lead-, candidate- and clinical phase projects in the antibiotic space, mostly from pharma and biotech for funders, and this outstanding paper is exceptional in its breadth, quality and potential impact.
The paper demonstrates what can be achieved through largely academic collaboration and appropriate funding – an example of the future for antibiotic discovery given the state of the industry.
It describes the output of a combination of activities by the European Lead Factory, the European Gram-negative Antibacterial Engine (ENABLE) (http://nd4bb-enable.eu/) and the University of Oxford which led to the identification of the novel warhead.
The programme covered biochemistry, chemistry, structural biology (over 50 structures were obtained), ADME and optimisation to reduce liabilities such as protein binding and metabolic stability and to improve potency against target MBLs.
Compound InC58 was identified which potentiated carbapenem activity against an impressive range of otherwise carbapenem-resistant clinically relevant strains. Looks like it may have useful activity against Enterobacterales but maybe not against P. aeruginosa and A. baumannii.
They used high hurdle animal models including neutropenic thigh models, allowed infection to develop for 1 hour prior to therapy and only administered a single dose of s.c meropenem with i.v. InC58 and assessed efficacy 3 hours later. This is an atypical short design of in vivo study. Others may have used multiple doses of meropenem, to mimic human pharmacokinetics, over a longer period e.g. 9 hours, to maximise effect. We need to wait and see what additional PK/PD studies show, but it looks very encouraging. With optimal dosing even greater efficacy may be anticipated, especially against K. pneumoniae.
I did not notice combinations of InC58 with serine lactamase inhibitors which may help coverage and I wonder how InC58 potentiates other lactam antibiotic activity e.g. temocillin against ESBL clinical isolates with a high prevalence of MBLs.
It will be interesting to see how the collaboration have managed the project intellectual property.
The project is advancing towards clinical trials and with the Ineos Oxford Institute’s funding and expertise they have every chance of success!
Building virtual pharma within and across academic organisations will be essential to create the critical mass of skills, expertise and experience needed to nurture antibiotic R&D post-industry collapse.