Assembly of a core peptidoglycan biosynthesis complex from Pseudomonas aeruginosa – BAC-ASSEMBLY

The cell wall is important for bacterial survival and shape, and its biosynthetic mechanism is the target of antibiotics such as beta-lactams and vancomycin. The spread of resistant strains, however, has thwarted the usefulness of these drugs and calls for efforts towards the understanding of processes that could lead to innovative treatments. One of the main pathogens signaled by the WHO as urgently necessitating novel treatment approaches is Pseudomonas aeruginosa, a Gram-negative organism that is the causative agent of hospital- and community-acquired infections, in addition to being a major threat for cystic fibrosis patients. In BAC-ASSEMBLY, we will continue our very successful collaboration in the study of the P. aeruginosa cell wall and will tackle the study of a cell wall-forming complex encompassing cytoplasmic, membrane, and periplasmic proteins.

Thanks to an ANR grant (PSEUDO-WALL) that also supported this partnership, Partners 1 and 2 took major steps forward in this field by structurally and functionally characterizing, for the first time, the oligomeric forms of the P. aeruginosa peptidoglycan scaffolding factor, MreC. These totally novel results suggested how such assemblies could participate in turning cell wall biosynthesis on/off, thus playing a key role in its regulation. In BAC-ASSEMBLY, we will go beyond these initial successful results, expanding our effort to characterize a three-compartment, multi-partner cell wall formation complex from P. aeruginosa using X-ray crystallography, electron microscopy, biochemistry, and microbiology techniques. Lastly, we will employ a genome-wide screen in a clinical strain to identify additional partners and regulators of this central P. aeruginosa cell wall formation complex, providing a fresh outlook on the search for new antimicrobials.