ß-Lactam antibiotics with a high affinity for pbp2 act synergistically with the ftsz-targeting agent txa707 against methicillin-resistant staphylococcus aureus

Edgar Ferrer-González, Malvika Kaul, Ajit K. Parhi, Edmond J. LaVoie, Daniel S. Pilcha

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen that poses a significant risk to global health today. We have developed a promising new FtsZ-targeting agent (TXA707) with potent activity against MRSA isolates resistant to current standard-of-care antibiotics. We present here results that demonstrate differing extents of synergy between TXA707 and a broad range of -lactam antibiotics (including six cephalosporins, two penicillins, and two carbapenems) against MRSA. To explore whether there is a correlation between the extent of synergy and the preferential antibacterial target of each -lactam, we determined the binding affinities of the -lactam antibiotics for each of the four native penicillin-binding proteins (PBPs) of S. aureus using a fluorescence anisotropy competition assay. A comparison of the resulting PBP binding affinities with our corresponding synergy results reveals that -lactams with a high affinity for PBP2 afford the greatest degree of synergy with TXA707 against MRSA. In addition, we present fluorescence and electron microscopy studies that suggest a potential mechanism underlying the synergy between TXA707 and the -lactam antibiotics. In this connection, our microscopy results show a disruption of septum formation in TXA707-treated MRSA cells, with a concomitant mislocalization of the PBPs from midcell to nonproductive peripheral sites. Viewed as a whole, our results indicate that PBP2-targeting -lactam antibiotics are optimal synergistic partners with FtsZ-targeting agents for use in combination therapy of MRSA infections.

Original languageEnglish (US)
Article numbere00863-17
JournalAntimicrobial agents and chemotherapy
Volume61
Issue number9
DOIs
StatePublished - Sep 2017

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Keywords

  • Combination therapy
  • FtsZ-targeting agents
  • MRSA
  • PBP binding affinity
  • PBP mislocalization
  • PBP2-targeting -lactam antibiotics
  • Synergy
  • TXA707

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