The resistance to β-lactam antibiotics, specifically against serious Gram-negative infections has been an emerging health threat. This resistance is primarily driven by the expression of β-lactamases, enzymes that deactivate β-lactam antibiotics. To combat this issue, we aimed to discover a novel monobactam antibiotic to be used in combination with our class A/C β-lactamase inhibitor, relebactam. Monobactams, an under-utilized class of β-lactam antibiotics, possess the unique advantage of being resistant to hydrolysis by class B metallo-β-lactamases, which are a major concern in β-lactam resistance.

In this presentation, we will discuss our efforts in optimizing the lead compound by improving its antibacterial activity, overcoming numerous challenges (solubility, stability, etc.) and balancing the compound's basicity (necessary to evade bacterial efflux mechanisms and enhance solubility) with issues related to histamine release and in vivo safety profile. Through cross-functional collaboration, we successfully discovered novel monobactam antibiotics that exhibit stability against not only class B metallo-β-lactamases but also class C, D, and some class A serine β-lactamases. When combined with relebactam, our molecules demonstrate broad-spectrum activity against multidrug-resistant gram-negative pathogens including carbapenem-resistant Acinetobacter and Enterobacterales, as well as P. aeruginosa. Our results indicate that this combination has the potential to provide a broader coverage than the currently available β-lactam/β-lactamase inhibitor combinations used in clinical practice.

Additionally, we will highlight key lessons learned from our monobactam program, including the utilization of label-free MALDI-MS imaging technology to assess nephrotoxicity potential in a resource-efficient manner, and the establishment of an adaptive phase screening workplan to tackle the challenging evaluation of crystalline solubility. Addressing these challenges in drug discovery could be beneficial to the medicinal chemistry community as a whole.

Coverage sepctrum of Gram-negative antibiotics

Alexander Pasternak PhD

Senior Principal Scientist, Merck

Appearances