Loss of GdpP function in Staphylococcus aureus leads to β-lactam tolerance and enhanced evolution of β-lactam resistance

Author:

Poon Raymond12,Basuino Li3,Satishkumar Nidhi12,Chatterjee Aditi12,Mukkayyan Nagaraja12,Buggeln Emma3,Huang Liusheng4,Nair Vinod5,Argudín Maria A.6ORCID,Datta Sandip K.7,Chambers Henry F.3,Chatterjee Som S.12

Affiliation:

1. Department of Microbial Pathogenesis, School of Dentistry, University of Maryland, Baltimore, MD, USA

2. Institute of Marine and Environmental Technology, Baltimore, MD, USA

3. Division of HIV/AIDS, Infectious Diseases and Global Health, Department of Medicine, University of California, San Francisco, San Francisco General Hospital, San Francisco, CA, USA

4. Drug Research Unit, Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA, USA

5. Microscopy Unit, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA

6. National Reference Centre for Staphylococcus aureus, Department of Microbiology, Laboratoire Hospitalier Universitaire de Bruxelles Universitair Laboratorium Brussel (LHUB-ULB), Université Libre de Bruxelles, Brussels, Belgium

7. Bacterial Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

Abstract

Infections caused by Staphylococcus aureus are a leading cause of mortality. Treating infections caused by S. aureus is difficult due to resistance against most traditional antibiotics, including β-lactams. We previously reported the presence of mutations in gdpP among S. aureus strains that were obtained by serial passaging in β-lactam drugs. Similar mutations have recently been reported in natural S. aureus isolates that are either non-susceptible or resistant to β-lactam antibiotics. gdpP codes for a phosphodiesterase that cleaves cyclic-di-AMP (CDA), a newly discovered second messenger. In this study, we sought to identify the role of gdpP in β-lactam resistance in S. aureus . Our results showed that gdpP associated mutations caused loss of phosphodiesterase function, leading to increased CDA accumulation in the bacterial cytosol. Deletion of gdpP led to an enhanced ability of the bacteria to withstand a β-lactam challenge (two to three log increase in bacterial colony forming units) by promoting tolerance without enhancing MICs of β-lactam antibiotics. Our results demonstrated that increased drug tolerance due to loss of GdpP function can provide a selective advantage in acquisition of high-level β-lactam resistance. Loss of GdpP function thus increases tolerance to β-lactams that can lead to its therapy failure and can permit β-lactam resistance to occur more readily.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference4 articles.

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