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. 2016 Jun 20;60(7):3934-41.
doi: 10.1128/AAC.00358-16. Print 2016 Jul.

PBP 4 Mediates High-Level Resistance to New-Generation Cephalosporins in Staphylococcus aureus

Liana C Chan  1 , Aubre Gilbert  1 , Li Basuino  1 , Thaina M da Costa  2 , Stephanie M Hamilton  1 , Katia R Dos Santos  3 , Henry F Chambers  1 , Som S Chatterjee  4
Affiliations

PBP 4 Mediates High-Level Resistance to New-Generation Cephalosporins in Staphylococcus aureus

Liana C Chan et al. Antimicrob Agents Chemother. .

Abstract

Staphylococcus aureus is an important cause of both hospital- and community-associated methicillin-resistant S. aureus (MRSA) infections worldwide. β-Lactam antibiotics are the drugs of choice to treat S. aureus infections, but resistance to these and other antibiotics make treatment problematic. High-level β-lactam resistance of S. aureus has always been attributed to the horizontally acquired penicillin binding protein 2a (PBP 2a) encoded by the mecA gene. Here, we show that S. aureus can also express high-level resistance to β-lactams, including new-generation broad-spectrum cephalosporins that are active against methicillin-resistant strains, through an uncanonical core genome-encoded penicillin binding protein, PBP 4, a nonessential enzyme previously considered not to be important for staphylococcal β-lactam resistance. Our results show that PBP 4 can mediate high-level resistance to β-lactams.

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Figures

FIG 1
FIG 1
Serial passaging of bacteria in ceftobiprole and ceftaroline. Bacteria were passaged every day in ceftobiprole or ceftaroline as described in Materials and Methods. (A) Strain SF8300ex passage in ceftobiprole (SRB) and ceftaroline (SRT). (B) Strain Sgap and Sp passage in ceftaroline.
FIG 2
FIG 2
Point mutations mapped on the PBP 4-cefotaxime complex. PBP 4 point mutations (yellow) detected in this study are depicted near the active site of cefotaxime-bound PBP 4 (PDB 3HUM).
FIG 3
FIG 3
Population analysis of the passaged strains and their isogenic Δpbp4 knockout strains in nafcillin. (A to D) Ten microliters of serially diluted bacterial overnight cultures was spotted onto agar plates containing various concentrations of nafcillin, as indicated. Bacterial colonies were enumerated (CFU ml−1) after 72 h of incubation at 37°C.
FIG 4
FIG 4
Population analysis of the complemented strains in nafcillin. (A and B) Ten microliters of serially diluted bacterial overnight cultures, as indicated, were spotted onto agar plates containing tetracycline (12.5 μg ml−1) and various concentrations of nafcillin, as indicated. Bacterial colonies were enumerated (CFU ml−1) after 72 h of incubation at 37°C. pbp4 (SF8300), pbp4 (SRB), and pbp4 (SRT) represent the pbp4 genes from strains SF8300, SRB, and SRT, respectively, that were cloned into pTXΔ and introduced into the indicated strains. Two-way ANOVA of the data revealed significant differences (P < 0.0001) between the strains.
FIG 5
FIG 5
Serial passaging of bacteria in nafcillin. Bacteria were passaged every day in nafcillin as described in Materials and Methods. Each day, the drug concentration at which visible bacterial growth was observed was plotted.
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