#Pbp3 pdb plus#

This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPEВ pathogens, Stenotrophomonas maltophilia and biothreat pathogens. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. Notably, the features that enhanced target potency were found to preclude compound uptake. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Diazabicyclooctane inhibitors retain activity in the presence of ОІ-lactamases, the primary resistance mechanism associated with ОІ-lactam therapy in Gram-negative bacteria 2, 3. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including ОІ-lactamase enzymes, stringent response and outer membrane permeation.

aeruginosa PBP3 and open avenues for future design of inhibitors of this class of PBPs.The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide 1. Taken together, these structural, biochemical, and computational studies provide a molecular basis for recognition of P. Energetic analysis of tightly and loosely held computed hydration sites indicates protein desolvation effects contribute significantly to PBP3 binding, and analysis of hydration site energies allows rank ordering of the second-order acylation rate constants. This is also the first example of a siderophore-conjugated triazolone-linked monocarbam complexed with any PBP. Importantly, we have identified a novel conformation that is distinct to the high-molecular-weight class B PBP subfamily, which is identifiable by common features such as a hydrophobic aromatic wall formed by Tyr503, Tyr532, and Phe533 and the structural flexibility of Tyr409 flanked by two glycine residues. The structure of MC-1, a new siderophore-conjugated monocarbam complexed with PBP3 provides molecular insights for lead optimization. aeruginosa PBP3 is due to a distinct hydrophobic aromatic wall composed of Tyr503, Tyr532, and Phe533 interacting with the gem-dimethyl group. The well-known affinity of the monobactam aztreonam for P. These structures reveal a conformational rearrangement of Tyr532 and Phe533 and a ligand-induced conformational change of Tyr409 and Arg489. aeruginosa PBP3 with both novel and marketed ОІ-lactams. Here we disclose the first high resolution cocrystal structures of the P. Penicillin-binding protein PBP3, a key therapeutic target, is an essential enzyme responsible for the final steps of peptidoglycan synthesis and is covalently inactivated by ОІ-lactam antibiotics.

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes nosocomial infections for which there are limited treatment options.

Pbp3 pdb