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Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: e00863-17. doi: 10.1128/AAC.00863-17. Print 2017 Sep.

β-Lactam Antibiotics with a High Affinity for PBP2 Act Synergistically with the FtsZ-Targeting Agent TXA707 against Methicillin-Resistant Staphylococcus aureus.

Author information

1
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
2
Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, New Jersey, USA.
3
TAXIS Pharmaceuticals, Inc., Monmouth Junction, New Jersey, USA.
4
Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, USA pilchds@rwjms.rutgers.edu.

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 β-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 β-lactam, we determined the binding affinities of the β-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 β-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 β-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 β-lactam antibiotics are optimal synergistic partners with FtsZ-targeting agents for use in combination therapy of MRSA infections.

KEYWORDS:

FtsZ-targeting agents; MRSA; PBP binding affinity; PBP mislocalization; PBP2-targeting β-lactam antibiotics; TXA707; combination therapy; synergy

PMID:
28630190
PMCID:
PMC5571351
DOI:
10.1128/AAC.00863-17
[Indexed for MEDLINE]
Free PMC Article

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