Discovery and Preclinical Development of ANT3310 a Broad-Spectrum Serine β-Lactamase Inhibitor which Potentiates Meropenem against Carbapenem Resistant Bacteria

David Davies
Antabio

Introduction/Background & aims Multidrug-resistant Gram-negative bacteria have become an increasingly serious healthcare threat, exacerbated by major structural and economic issues underlying development of new antibacterial drugs.¹ The effectiveness of the most important class of antibacterial agents, the β-lactam antibiotics, has been compromised by a main resistance mechanism, the production of β-lactamase enzymes. Co-dosing of β-lactams with a β-lactamase inhibitor (BLI) has been used for many years as a successful strategy to combat this type of resistance. However the older BLIs have become less clinically useful due to increasing resistance attributable to bacterial production of extended spectrum β-lactamases (ESBLs). In 2015, the novel diazabicyclooctane (DBO) BLI avibactam entered the clinic in fixed combination with ceftazidime and several “fast followers”, including relebactam, nacubactam, zidebactam and durlobactam, all bearing an amide substituent.

Method/Summary of work However, none of these, with the exception of durlobactam, penetrate/accumulate into Acinetobacter strains and, since durlobactam is not active against Enterobacterales, a combination to treat both carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Acinetobacter baumannii (CRAB)² infections remains elusive. At the outset of this research we set ourselves the objective of achieving a broad-spectrum DBO that also restored carbapenem activity against CRAB.

Results/Discussion Herein we describe the short medicinal chemistry campaign to successfully achieve this novel and desirable profile. We also describe PK, efficacy and X-ray studies plus early CMC/preclinical studies on the route towards Phase 1.

Conclusion(s) Please note this presentation describes a large amount of very different types of research in drug discovery and hence the abstract does not properly fit into the above boxes in the website.

Reference(s)

1. O’Neill, J. 2016, Review on Antimicrobial Resistance, Antimicrobial Resistance: Tackling a Crisis for the Health and Wealth of Nations https://amr-review.org/home.html

2. Global Priority List of Antibiotic-Resistant Bacterial to guide Research, Discovery and Development of New Antibiotics, World Health Organisation, https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf