Abstract
Novel antimicrobial strategies are urgently required because of the rising threat of multi drug resistant bacterial strains and the infections caused by them. Among the available target structures, the so-called penicillin binding proteins are of particular interest, owing to their good accessibility in the periplasmic space, and the lack of homologous proteins in humans, reducing the risk of side effects of potential drugs. In this report, we focus on the interaction of the innovative β-lactam antibiotic AIC499 with penicillin binding protein 3 (PBP3) from Escherichia coli and Pseudomonas aeruginosa. This recently developed monobactam displays broad antimicrobial activity, against Gram-negative strains, and improved resistance to most classes of β-lactamases. By analyzing crystal structures of the respective complexes, we were able to explore the binding mode of AIC499 to its target proteins. In addition, the apo structures determined for PBP3, from P. aeruginosa and the catalytic transpeptidase domain of the E. coli orthologue, provide new insights into the dynamics of these proteins and the impact of drug binding.
Highlights
Published: 19 July 2021In 2014, the WHO published an alarming report about the increasing proportion of multi drug resistant (MDR) bacterial strains in human infections, which is insufficiently accounted for by the development of new antibacterials and was declared one of the most important public health threats of the 21st century [1]
We aim to explore the X-ray structures of covalent intermediates formed with penicillin binding protein 3 (PBP3) from E. coli and P. aeruginosa to rationalize the binding mechanism of the five functional groups in AIC499
PBP3 from E. coli was produced as a soluble version in which the
Summary
In 2014, the WHO published an alarming report about the increasing proportion of multi drug resistant (MDR) bacterial strains in human infections, which is insufficiently accounted for by the development of new antibacterials and was declared one of the most important public health threats of the 21st century [1]. Named after their ability to interact with penicillin, penicillin binding proteins (PBPs) are well established targets of a larger family of antibiotics containing a β-lactam moiety [2]. Synthesis of PG requires glycosyltransferase (GTase) activity for joining GlcNAc-MurNAc disaccharides, which are available as a membraneanchored precursor (lipid II), to the growing chain, and transpeptidase (TPase) activity for establishing peptide cross-links.
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