Acinetobacter baumannii is one of the most challenging bacterial pathogens threatening modern medicine. Its global significance stems from the rapid development of multidrug resistance, rendering clinical eradication notoriously difficult. The A. baumannii envelope is a superior permeability barrier against antibiotic assault, of which the phospholipid component is maintained through highly coordinated lipid synthetic pathways giving rise to diverse species. This is critical to the biophysical properties of the cell membrane and the function of integral membrane proteins, such as those involved in antibiotic efflux.
In this study, we sought to elucidate the roles of A. baumannii PgpA and PgpB, two phosphatases implicated in the biosynthesis of the major anionic phospholipid, phosphatidylglycerol. Our phospholipid analyses revealed a specific shift in its composition following the inactivation of pgpA, but not pgpB, in two distinct A. baumannii strains. Further, resistance analyses illustrated that PgpA is critical for aminoglycoside resistance, independent of the A. baumannii multidrug efflux system AdeABC. We also investigated the impact of these phosphatases on other cell envelope components, which revealed a role of PgpB in the maintenance of peptidoglycan, and carbapenem resistance. Additionally, the inactivation of pgpA decreased the relative abundance of lipid A, but did not influence colistin resistance.
Collectively, this work provides novel insights into the roles of membrane phosphatases on the global landscape of the A. baumannii cell envelope. Our findings reveal that cell envelope biology should be examined holistically, due to the interconnectivity observed between its distinct layers.