Novel Small Molecule Potential to Treat Carbapenem-Resistant Entereobacteriace (CRE) Infections

AMR is a global unmet health problem. The solutions developed i.e. effective novel pan-MBLs inhibitors have the potential to be sold globally and hence have high potential commercial value. Considering fewer ongoing efforts and huge unmet medical needs, many big and small pharmaceutical industries (national and international), will be interested to in-license any potential molecule showing promise in treating AMR infections.

Beta-lactam antibiotics are the cornerstones of antimicrobial chemotherapy. However, antimicrobial resistance against these life-saving drugs is a major public health problem worldwide. Resistance to beta-lactam antibiotics among Gram-negative bacteria is mainly due to the production of beta-lactamases, which inactivate these life-saving drugs. Bacteria achieve resistance by these challenging chemical reactions with two types of enzymes: serine β-lactamases and/or metallo-β-lactamases (MBL). Recently few serine beta-lactamase inhibitors have been approved, but to date, not a single MBL inhibitor is approved or in the clinic. So, there is an urgent unmet medical need to discover a new ideal MBL inhibitor, which can be used as an adjuvant with FDA-approved beta-lactam antibiotics and would be beneficial in difficult-to-treat hospital-based infections.

The salient features of this technology are:

• First-in-class novel small molecule MBL inhibitor is discovered.
• Discovered novel compounds showed IC₅₀ in nano-molar range activity against more clinical relavance pathogens NDM-1, VIM-1 and IMP-1.
• Compounds showed synergy with last-resort antibiotics (Meropenem and Imipenem) in carbapenem-resistant strain.  
• Library of compounds prepared, tested against NDM-1, VIM and IMP-1 gene, evaluated synergy, and analysed structure-activity relationship (SAR).
• Novel small molecule inhibitor can be use as adjuvant with antibiotic to address difficult to treat hospital-acquired / Carbapenem-Resistant Enterobacteriaceae (CRE) infections.
• The lead compounds showed good physio-chemical properties (logD and solubility)
• In vitro ADME and toxicity data showed promising results.
• In preliminary in vivo animal study, lead compound showed efficacy in thigh infection model in combination with last resort antibiotic (Imipenem).
• Low cost synthesis and process optimized for the lead compounds.
• Detailed PK/PD studies in progress