Research ArticleMRSA

Restoring Methicillin-Resistant Staphylococcus aureus Susceptibility to β-Lactam Antibiotics

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Science Translational Medicine  21 Mar 2012:
Vol. 4, Issue 126, pp. 126ra35
DOI: 10.1126/scitranslmed.3003592

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A Drug Duet to Combat MRSA

Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of bloodstream infections in hospitals worldwide. MRSA infection rates in the United States reported as recently as 2005 estimate that mortality associated with MRSA exceeded that of HIV/AIDS in the same year. Compounding this issue is the rapid emergence of community-acquired MRSA infections in healthy individuals and the difficulty within the pharmaceutical industry regarding discovery of new and efficacious single-agent antibiotics to treat bacterial pathogens resistant to traditional antibiotics. MRSA drug resistance is attributed to the acquisition of an accessory penicillin-binding protein (PBP2A), which is refractory to the inhibitory activity of penicillin and other β-lactam antibiotics. To thwart this resistance mechanism, Tan et al. sought to identify alternative drug targets that, when inhibited by genetic means, resensitized MRSA to β-lactam antibiotics. They discovered that a target class displaying this phenotype in S. aureus comprised proteins involved in cell division including FtsZ, the bacterial ancestor of tubulin. The researchers then demonstrated that the FtsZ-specific inhibitor PC190723 acts synergistically with β-lactam antibiotics in vitro and in vivo and that this combination was efficacious in a mouse model of MRSA infection. Fluorescence microscopy localization studies revealed that the chemical synergy between these agents is likely to be elicited by the concomitant delocalization of their drug targets: FtsZ and PBP2. Next, the authors resolved a 2.0 Å crystal structure of S. aureus FtsZ in complex with PC190723 and identified mutations in FtsZ that confer resistance against PC190723 on MRSA. However, combining PC190723 with a β-lactam antibiotic markedly reduced the spontaneous frequency with which PC190723 drug resistance mutations emerged in MRSA. Moreover, MRSA with PC190723 resistance mutations displayed attenuated virulence and restored susceptibility to β-lactam antibiotics. Together, these data support a target-based approach to develop synergistic drug combinations to combat MRSA with improved efficacy and reduced potential for drug resistance.