Oral Metallo-Beta-Lactamase Inhibitors: Exploiting Reaction Mechanisms

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Gram-negative pathogens producing metallo-β-lactamases, MBLs, are a significant threat to our public health as treatment options against bacteria possessing these resistance determinants are extremely limited. In general, MBLs are the most worrisome carbapenemases, inactivating “last resort” β-lactams (e.g., imipenem and meropenem) and resist all commercially available β-lactamase inhibitors (BLIs). The main challenge in MBL inhibitor design is exploiting the reaction mechanism as it relates to the structural diversity of the 3 distinct subclasses (B1, B2, and B3). Based on this approach, our consortium has successfully designed a series of innovative compounds, bisthiazolidines (BTZs) and thiazolidines (TZs), inspired on a non-β-lactam “penicillin core” decorated with specific metal binding groups. To date, BTZs and TZs are unique potent, non- toxic, “cross-class” MBL inhibitors. Recently, we determined the structural basis of their inhibitory action, and their microbiological activity (bactericidal when combined with a carbapenem). This inspires confidence in the ability of BTZs and TZs to be effective against MBL producing Gram-negative bacteria. Interestingly, novel TZs exhibit similar properties and potencies and in certain cases are superior to BTZs. The overarching objectives of this project are to embark upon a “high risk-high reward” program in drug discovery to develop an effective oral MBL inhibitor that is absorbed sufficiently from the gastrointestinal (GI) tract and can be partnered with an oral carbapenem, tebipenem pivoxil (Tbp-Pvx). We are co-opting an established strategy, the addition of a pivoxil group, which has been successful in at least two commercial formulations (cefditoren pivoxil and tebipenem pivoxil) and adapting it to our developmental compounds (BTZs and TZs). Since parenteral inhibitors for serine carbapenemases are already in clinical use (e.g., avibactam, relebactam and vaborbactam) and only a few truly MBL inhibitors are in development (QPX7728 and taniborbactam), our unique and specific formulation will address an unmet medical need, i.e. that of an oral cross-subclass MBL inhibitor. By the nature of its components, Tbp-Pvx is also intended to be stable against extended-spectrum β-lactamases (ESBLs) and class C cephalosporinases (AmpCs), which are resistance determinants often present in MBL-producing strains. Additionally, we will mitigate the problems associated with cephalosporins (resistance selection). As a lead compound, we have identified a potent BTZ (L syn CS319) that effectively lowers MICs to within the susceptible range when paired with a carbapenem. As an alternative, we have also synthesized potent TZ derivatives. We propose to develop the first oral carbapenem and MBL inhibitor formulation to be considered for development that overcomes difficult to treat carbapenem resistant infections mediated by MBLs. Our experimental evaluations stem from close partnership with scientists in Argentina and Uruguay and will involve a closer collaboration with the Wound Infections Department (WID) and the Experimental Therapeutics (ET) Branch of the Walter Reed Army Institute of Research (WRAIR) via the Geneva Foundation. After establishing “proof of concept” in the murine thigh infection model, the ultimate clinical applications will be in skin and soft tissue, and bone and joint infections. These are clear priorities for the Veterans Health Administration and the US Military.