A Dysfunctional Tricarboxylic Acid Cycle Enhances Fitness of <named-content content-type="genus-species">Staphylococcus epidermidis</named-content> During β-Lactam Stress
Vinai Chittezham Thomas,
Lauren C. Kinkead,
Ashley Janssen,
Carolyn R. Schaeffer,
Keith M. Woods,
Jill K. Lindgren,
Jonathan M. Peaster,
Sujata S. Chaudhari,
Marat Sadykov,
Joselyn Jones,
Sameh M. Mohamadi AbdelGhani,
Matthew C. Zimmerman,
Kenneth W. Bayles,
Greg A. Somerville,
Paul D. Fey
Affiliations
Vinai Chittezham Thomas
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Lauren C. Kinkead
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Ashley Janssen
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Carolyn R. Schaeffer
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Keith M. Woods
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Jill K. Lindgren
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Jonathan M. Peaster
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Sujata S. Chaudhari
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Marat Sadykov
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Joselyn Jones
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
Sameh M. Mohamadi AbdelGhani
Department of Microbiology and Immunology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
Matthew C. Zimmerman
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
Kenneth W. Bayles
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
Greg A. Somerville
School of Veterinary Medicine and Biomedical Sciences, University of Nebraska, Lincoln, Lincoln, Nebraska, USA
Paul D. Fey
Department of Pathology and Microbiology, Center for Staphylococcal Research, University of Nebraska Medical Center, Omaha, Nebraska, USA
ABSTRACT A recent controversial hypothesis suggested that the bactericidal action of antibiotics is due to the generation of endogenous reactive oxygen species (ROS), a process requiring the citric acid cycle (tricarboxylic acid [TCA] cycle). To test this hypothesis, we assessed the ability of oxacillin to induce ROS production and cell death in Staphylococcus epidermidis strain 1457 and an isogenic citric acid cycle mutant. Our results confirm a contributory role for TCA-dependent ROS in enhancing susceptibility of S. epidermidis toward β-lactam antibiotics and also revealed a propensity for clinical isolates to accumulate TCA cycle dysfunctions presumably as a way to tolerate these antibiotics. The increased protection from β-lactam antibiotics could result from pleiotropic effects of a dysfunctional TCA cycle, including increased resistance to oxidative stress, reduced susceptibility to autolysis, and a more positively charged cell surface. IMPORTANCE Staphylococcus epidermidis, a normal inhabitant of the human skin microflora, is the most common cause of indwelling medical device infections. In the present study, we analyzed 126 clinical S. epidermidis isolates and discovered that tricarboxylic acid (TCA) cycle dysfunctions are relatively common in the clinical environment. We determined that a dysfunctional TCA cycle enables S. epidermidis to resist oxidative stress and alter its cell surface properties, making it less susceptible to β-lactam antibiotics.
