Abstract
AbstractMethicillin‐resistant Staphylococcus aureus (MRSA) tolerates β‐lactam antibiotics by carrying out cell wall synthesis with the transpeptidase Penicillin‐binding protein 2a (PBP2a), which cannot be inhibited by β‐lactams. It has been proposed that PBP2a's active site is protected by two loops to reduce the probability of it binding with β‐lactams. Previous crystallographic studies suggested that this protected active site opens for reaction once a native substrate binds at an allosteric domain of PBP2a. This opening was proposed for the new β‐lactam ceftaroline's mechanism in successfully treating MRSA infections, i. e. by it binding to the allosteric site, thereby opening the active site to inhibition. In this work, we investigate the binding of ceftaroline at this proposed allosteric site using molecular dynamics simulations. Unstable binding was observed using the major force fields CHARMM36 and Amber ff14SB, and free energy calculations were unable to confirm a strong allosteric effect. Our study suggests that the allosteric effect induced by ceftaroline is weak at best.
Highlights
Ever since Sir Alexander Fleming discovered penicillin in 1928, β-lactams – the core structure for all penicillin-like antibiotics (Figure 1A) – have saved numerous lives and are still regularly used against bacteria. β-lactams target the transpeptidase enzyme involved in bacterial cell wall synthesis
Resistance to methicillin was reported shortly after its introduction;[3] Staphylococcus aureus brought in a new transpeptidase – Penicillin-binding protein 2a (PBP2a) – that did not interact with methicillin and had unhindered cell wall synthesis
We report the results from our molecular dynamics (MD) simulations of PBP2a with ceftaroline at both the allosteric and active sites, using both CHARMM36[11,12] and Amber ff14SB[13] force fields
Summary
Ever since Sir Alexander Fleming discovered penicillin in 1928, β-lactams – the core structure for all penicillin-like antibiotics (Figure 1A) – have saved numerous lives and are still regularly used against bacteria. β-lactams target the transpeptidase enzyme involved in bacterial cell wall synthesis. As early as 1942, penicillin-resistant staphylococci were already appearing in hospitals, roughly the same time when penicillin was first used to treat disease.[3] Soon it was identified that those strains produced an enzyme called penicillinase to break down penicillin.[4] Penicillinase-type enzymes (so called β-lactamases) quickly spread across various species, leading to a wave of penicillin resistance Following this resistance, new drugs were developed. Resistance to methicillin was reported shortly after its introduction;[3] Staphylococcus aureus brought in a new transpeptidase – PBP2a – that did not interact with methicillin and had unhindered cell wall synthesis. This pressure was partially relieved in 2010, when the new drug ceftaroline (a fifthgeneration β-lactam) was approved
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