Penicillin-binding protein (PBP) 3 is essential for growth of P. aeruginosa [PublishAheadOfPrint]

Penicillin-binding proteins (PBPs) function as transpeptidases, carboxypeptidases or endopeptidases during peptidoglycan synthesis in bacteria. As the well-known drug targets for β-lactam antibiotics, the physiological functions of PBPs and whether they are essential for growth is of significant interest. The pathogen Pseudomonas aeruginosa (Pa) poses a particular risk to immunocompromised and cystic fibrosis patients, and is difficult to treat due to antibiotic resistance. To identify potential drug targets among the PBPs in Pa, we performed gene knockouts of all the high-molecular mass (HMM) PBPs and determined impacts on cell growth and morphology, susceptibility to β-lactams, peptidoglycan structure, virulence, and pathogenicity. Disruptions of the transpeptidase domains of most HMM PBPs, including double disruptions, had only minimal effects on cell growth. The exception was PBP3, where cell growth only occurred when the protein was conditionally expressed on an integrated plasmid. Conditional deletion of PBP3 also caused a defect in cell division and increased susceptibility to β-lactams. Knockout of PBP1a led to impaired motility, and together with its localization at the cell poles, suggests an involvement in flagellar function. Overall, these findings reveal that PBP3 represents the most promising target for drug discovery against Pa, whereas other HMM PBPs have less potential.

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