Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most prevalent multidrug-resistant pathogens worldwide, exhibiting increasing resistance to the latest antibiotic therapies. Here we show that the triple β-lactam combination meropenem/piperacillin/tazobactam (ME/PI/TZ) acts synergistically and is bactericidal against MRSA N315 and 72 clinical MRSA isolates in vitro, and clears MRSA N315 infection in a mouse model. ME/PI/TZ suppresses evolution of resistance in MRSA via reciprocal collateral sensitivity of its constituents. We demonstrate that these activities also extend to other carbapenem/penicillin/β-lactamase inhibitor combinations. ME/PI/TZ circumvents the tight regulation of the mec and bla operons in MRSA, the basis for inducible resistance to β-lactam antibiotics. Furthermore, ME/PI/TZ subverts the function of penicillin-binding protein 2a (PBP2a) action via allostery, which we propose as the mechanism for both synergy and collateral sensitivity. Showing similar in vivo activity to linezolid, ME/PI/TZ demonstrates that combinations of older β-lactam antibiotics could be effective against MRSA infections in humans.

β-Lactamase Inhibitors Enhance the Synergy between β-Lactam Antibiotics and Daptomycin against Methicillin-Resistant Staphylococcus aureus

“…In a series of in vitro experiments, Gonzales et al have demonstrated that the MEM-PIP-TAZ combination not only resulted in strong synergistic killing of MRSA but also suppressed the development of resistance, an effect that was not seen in the MEM-PIP combination (16). Interestingly, we found a suppressive effect similar to this with the DAP-TOL-TAZ combination (9).…”

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

“…Seventeen three‐drug combinations were effective against the drug‐resistant pathogen at clinically reachable individual drug concentrations. Another group also reported the strong synergy between meropenem, piperacillin and tazobactam against MRSA (Gonzales et al , 2015). The concentrations of individual drugs in the combinations are lower than the clinical susceptibility break points that are required for the clinical applications.…”

β-Lactams and β-Lactamase Inhibitors: An Overview

“…The resulting inactive acyl enzyme may then slowly hydrolyze the antibiotic to form a microbiologically inactive entity (Frère and Joris 1985). In addition to these functionalities, recent work has shown the binding of selected b-lactams, such as ceftaroline, to an allosteric site in PBP2a from Staphylococcus aureus, resulting in an increased sensitization of the organism to the antibiotic (Otero et al 2013;Gonzales et al 2015).…”