M676, a Putative Inhibitor of Undecaprenyl Pyrophosphate Synthase, Synergizes with 946;-lactam Antibiotics Against MRSA

Ref ID: 18772

Author:

L. Miesel, PhD (Doctor of Philosophy) – Biology Collaboration Lead, Infectious Diseases1, J. Baysarowich, MS – Team Member 2, A. Caron, MS – Team member, Pharmacology 3, J. Huber, MS – Research Assistant 2, M. Kavana, PhD – In Vitro Pharm Biochem Bio

Author address:

1Merck Res. Labs, Kenilworth, NJ, 2Merck Res. Labs, Rahway, NJ, 3Merck Res. Labs, Kirkland, Canada, 4Merck Res. Labs, West Point, PA.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: This study aimed to identify an agent that synergizes with β -lactam antibiotics to develop a combination therapy for MRSA. A whole cell screen for β -lactam potentiatiors yielded hit compound M676, a benzophenone oxime. Methods: The in vitro antibacterial activity and synergy with imipenem (IPM) was tested against MRSA clinical isolates with checkerboard analysis. Efficacy was measured with a murine thigh infection model. The mechanism of action was determined using a genetic approach: resistant mutants were selected and elucidated using NimbleGen’s Comparative Genome Sequencing (CGS). Biacore was used to measure binding to UppS. Results: M676 inhibited growth of MRSA isolates (MIC90 = 2 mg/L) and sensitized them to IPM (0.25 mg/L M676 reduced the IPM MIC to its susceptibility breakpoint of 4 mg/L). M676 demonstrated potent synergy in vitro with carbapenems, penicillins, and cephalosporins. Efficacy and synergy were observed in the murine thigh model with a four-log reduction of CFU from M676 (40 mg/kg) in combination with IPM (5 mg/kg). Two mutants resistant to M676 had the same mutation in the uppS gene resulting in an A76V substitution. M676 bound to the UppS enzyme with an estimated Kd of 3.7 µM. Decreased binding was observed to the A76V mutant UppS. Conclusions: M676 synergizes with β -lactam antibiotics in vitro and in vivo possibly by interfering with UppS function.

Abstract Number: F-1496

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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