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*AMMONIUM CHLORIDE
*CLOXACILLIN
*PENICILLIN G
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Antimicrobial Agents and Chemotherapy, May 2007, p. 1627-1632, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01192-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Role of Acidic pH in the Susceptibility of Intraphagocytic Methicillin-Resistant Staphylococcus aureus Strains to Meropenem and Cloxacillin{triangledown}

Sandrine Lemaire,1 Françoise Van Bambeke,1 Marie-Paule Mingeot-Leclercq,1 Youri Glupczynski,2 and Paul M. Tulkens1*

Unité de Pharmacologie cellulaire et moléculaire, Université catholique de Louvain, Brussels,1 Laboratoire de Microbiologie, Cliniques universitaires de Mont-Godinne, Yvoir, Belgium2

Received 22 September 2006/ Returned for modification 13 January 2007/ Accepted 3 February 2007

Early studies showed that methicillin-resistant Staphylococcus aureus (MRSA) strains are susceptible to β-lactams when they are exposed to pH ≤ 5.5 in broth. Because S. aureus survives in the phagolysosomes of macrophages, where the pH may be acidic, we have examined the susceptibility of MRSA ATCC 33591 phagocytized by human THP-1 macrophages to meropenem (MEM) and cloxacillin (CLX). Using a pharmacodynamic model assessing key pharmacological (50% effective concentration and maximal efficacy) and microbiological (static concentration) descriptors of antibiotic activity, we show that intraphagocytic MRSA strains are as sensitive to MEM and CLX as methicillin-susceptible S. aureus (MSSA; ATCC 25923). This observation was replicated in broth if the pH was brought to 5.5 and was confirmed with clinical strains. Electron microscopy showed that both the MRSA and the MSSA strains localized and multiplied in membrane-bounded structures (phagolysosomes) in the absence of β-lactams. Incubation of the infected macrophages with ammonium chloride (to raise the phagolysosomal pH) made MRSA insensitive to MEM and CLX. No difference was seen in mec, mecA, mecI, mecR1, femA, and femB expression (reversed transcription-PCR) or in PBP 2a content (immunodetection) in MRSA grown in broth at pH 5.5 compared with that in MRSA grown in broth at 7.4. The level of [14C]benzylpenicillin binding to cell walls prepared from a non-β-lactamase-producing MRSA clinical isolate was two times lower than that to cell walls prepared from MSSA ATCC 25923 at pH 7.4, but the levels increased to similar values for both strains at pH 5.5. These data suggest that the restoration of susceptibility of intraphagocytic of MRSA to MEM and CLX is due to the acidic pH prevailing in phagolysosomes and is mediated by an enhanced binding to penicillin-binding proteins.

* Corresponding author. Mailing address: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, UCL 73.70 Avenue E. Mounier 73, B-1200 Brussels, Belgium. Phone: 32-2-762.21.3. Fax: 32-2-764.73.73. E-mail: tulkens{at}facm.ucl.ac.be

{triangledown} Published ahead of print on 16 February 2007.

Antimicrobial Agents and Chemotherapy, May 2007, p. 1627-1632, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01192-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lemaire, S., Glupczynski, Y., Duval, V., Joris, B., Tulkens, P. M., Van Bambeke, F. (2009). Activities of Ceftobiprole and Other Cephalosporins against Extracellular and Intracellular (THP-1 Macrophages and Keratinocytes) Forms of Methicillin-Susceptible and Methicillin-Resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 53: 2289-2297 [Abstract] [Full Text]  
  • Lemaire, S., Olivier, A., Van Bambeke, F., Tulkens, P. M., Appelbaum, P. C., Glupczynski, Y. (2008). Restoration of Susceptibility of Intracellular Methicillin-Resistant Staphylococcus aureus to {beta}-Lactams: Comparison of Strains, Cells, and Antibiotics. Antimicrob. Agents Chemother. 52: 2797-2805 [Abstract] [Full Text]  
  • Lemaire, S., Fuda, C., Van Bambeke, F., Tulkens, P. M., Mobashery, S. (2008). Restoration of Susceptibility of Methicillin-resistant Staphylococcus aureus to {beta}-Lactam Antibiotics by Acidic pH: ROLE OF PENICILLIN-BINDING PROTEIN PBP 2a. J. Biol. Chem. 283: 12769-12776 [Abstract] [Full Text]  


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