Disruption of Allosteric Response as an Unprecedented Mechanism of Resistance to Antibiotics
نویسندگان
چکیده
Ceftaroline, a recently approved β-lactam antibiotic for treatment of infections by methicillin-resistant Staphylococcus aureus (MRSA), is able to inhibit penicillin-binding protein 2a (PBP2a) by triggering an allosteric conformational change that leads to the opening of the active site. The opened active site is now vulnerable to inhibition by a second molecule of ceftaroline, an event that impairs cell-wall biosynthesis and leads to bacterial death. The triggering of the allosteric effect takes place by binding of the first antibiotic molecule 60 Å away from the active site of PBP2a within the core of the allosteric site. We document, by kinetic studies and by determination of three X-ray structures of the mutant variants of PBP2a that result in resistance to ceftaroline, that the effect of these clinical mutants is the disruption of the allosteric trigger in this important protein in MRSA. This is an unprecedented mechanism for antibiotic resistance.
منابع مشابه
Detection of Mutations of Antimutator Gene pfpI in Pseudomonas aeruginosa Species Isolated from Burn Patients in Tehran, Iran
Introduction: Pseudomonas aeruginosa is an opportunistic pathogen of clinical importance, particularly in immunocompromised and burn patients. This bacterium is becoming resistant to many antibiotics via intrinsic or acquired mechanisms. Mutations in anti-mutator genes, such as pfpI, can be a potential intrinsic mechanism of antibiotic resistance. This study aimed to evaluate the possible effec...
متن کاملStudy of antimicrobial effects of several antibiotics and iron oxide nanoparticles on biofilm producing pseudomonas aeruginosa
Objective(s): Pseudomonas aeruginosa is a nosocomial pathogen resistant to most antimicrobial treatments. Furthermore, it persists in adverse environments thereby forming biofilms on various surfaces. Researchers have therefore focused on antibiofilm strategies using nanoparticles due to their unique physicochemical properties. Superparamagnetic iron oxide nanoparticles (SIONPs) have recently s...
متن کاملHow allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function.
The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The high-molecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that com...
متن کاملPrevalence of Microorganisms Causing Septicemia and Determination of Antimicrobial Resistance in Intensive Care Unit
The objective of this study was to determine the frequency of microorganisms isolated from blood samples of patients admitted to Intensive Care Unit (ICU), and the rate of their resistance to common administered antibiotics in an Iranian ICU. One-hundred patients with Systemic Inflammatory Response Syndromes (SIRS), hospitalized in ICU of Sina Hospital, Tehran, Iran, were entered to this cross-...
متن کاملPrevalence of Microorganisms Causing Septicemia and Determination of Antimicrobial Resistance in Intensive Care Unit
The objective of this study was to determine the frequency of microorganisms isolated from blood samples of patients admitted to Intensive Care Unit (ICU), and the rate of their resistance to common administered antibiotics in an Iranian ICU. One-hundred patients with Systemic Inflammatory Response Syndromes (SIRS), hospitalized in ICU of Sina Hospital, Tehran, Iran, were entered to this cross-...
متن کامل