Penicillin Binding Protein 7/8 Is a Potential Drug Target in Carbapenem-Resistant Acinetobacter baumannii

Area of Science:

• Microbiology
• Drug Discovery
• Antimicrobial Resistance

Background:

• Carbapenem-resistant Acinetobacter baumannii (CR A. baumannii) poses a significant global health threat due to limited treatment options.
• Identifying novel drug targets is crucial for developing new therapies against multidrug-resistant bacteria.

Purpose of the Study:

• To validate penicillin binding protein 7/8 (PBP 7/8) as a high-value drug target in CR A. baumannii.
• To investigate the phenotypic consequences of PBP 7/8 inactivation in CR A. baumannii.

Main Methods:

• Inactivation of PBP 7/8 in the CR A. baumannii strain HUMC1.
• Assessment of bacterial survival and virulence in various infection models (human ascites, rat abscess, mouse pneumonia).
• Analysis of bacterial cell envelope properties, including permeability, lysozyme sensitivity, and lipid A composition.

Main Results:

• PBP 7/8 is essential for CR A. baumannii survival and virulence, with its absence reducing lethality in a mouse pneumonia model by 11-fold.
• Loss of PBP 7/8 leads to increased cell permeability, heightened sensitivity to complement and lysozyme, and altered cell morphology.
• The PBP 7/8 mutant exhibits increased susceptibility to various antimicrobials without significant changes in AmpC expression or capsule production.

Conclusions:

• PBP 7/8 is a validated and high-value drug target for developing novel therapeutics against extensively drug-resistant and CR A. baumannii.
• The increased sensitivity of PBP 7/8 mutants to lysozyme provides a basis for developing high-throughput screening assays to identify PBP 7/8 inhibitors.