Investigating the role of the uncharacterized gene ygfB in the resistance of multidrug resistant Pseudomonas aeruginosa to β-lactam antibiotics

• Applicant: Dr. Erwin Bohn
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451686679

The hyperproduction of the ß-lactamase AmpC is an important cause of resistance to ß-lactams in Pseudomonas aeruginosa (Pa). While Pa ampC expression is known to depend on the transcriptional activator AmpR, the signals that enable AmpC hyperproduction remain elusive. A better understanding of such factors could help develop novel therapeutic strategies against multidrug resistant Pa strains, which are becoming increasingly prevalent in health care settings.AmpC hyperproduction is most frequently caused by inactivation of the genes dacB and ampD, which encode for the penicillin-binding protein PBP4 and the peptidoglycan-recycling amidase AmpD, respectively. The key events leading to ß-lactam resistance as a result of PBP4 inactivation seem to be (i) a high production of anhydro-MurNac-pentapeptides, which effectively derepress AmpR, and (ii) the activation of the two component system CreBC. How activation of CreBC contributes to ß-lactam resistance is unclear.In a recent study we identified the genes that contribute the most to ß-lactam resistance in the AmpC hyper-producing Pa clinical isolate ID40, a strain which carries a loss of function mutation in dacB. One of the genes we found to be crucial for full ß-lactam resistance is the uncharacterized gene ygfB. Preliminary studies suggest that YgfB transcriptionally represses the ampD paralogue encoding for the amidase AmpDh3 in ID40. Deletion of ygfB upregulates ampDh3 expression, which, in turn, leads to decreased ampC expression. These data suggest that the transcriptional repression of ampDh3 is critical to ensure high AmpC levels in a dacB mutant. In the proposed study, we want to elucidate in detail how YgfB contributes to antibiotic resistance in Pa.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Monika Schütz