Differential Regulation of ponA and pilMNOPQ Expression by the MtrR Transcriptional Regulatory Protein in Neisseria gonorrhoeae

Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA, Laboratories of Bacterial Pathogenesis, VA Medical Center, Decatur, Georgia 30033 and Department of Pharmacology, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, North Carolina

^* To whom correspondence should be addressed. Email: wshafer{at}emory.edu.

	Abstract

Neisseria gonorrhoeae utilizes the mtrCDE-encoded efflux pump system to resist not only host-derived, hydrophobic antimicrobials that bathe mucosal surfaces, which likely aids in its ability to colonize and infect numerous sites within the human host, but also antibiotics that have been used clinically to treat infections. Recently, over-expression of the MtrC-MtrD-MtrE efflux pump was shown to be critically involved in the capacity of gonococci to develop chromosomally-mediated resistance to penicillin G, which for over 40 years was used to treat gonococcal infections. Mutations in either the promoter or coding sequence of the mtrR gene, which encodes a repressor of the efflux pump operon, decrease gonococcal susceptibility to penicillin. We now describe the capacity of MtrR to directly or indirectly influence the expression of two other loci that are involved in gonococcal susceptibility to penicillin: ponA, which encodes penicillin-binding protein 1 (PBP 1), and the pilMNOPQ operon, which encodes components of the type IV pilus secretion system, with PilQ acting as a channel for entry for penicillin. We determined that MtrR increases expression of ponA directly or indirectly, resulting in increased levels of PBP 1, while repressing expression of the divergently transcribed pilM gene, the first gene in the pilMNOPQ operon. Taken together with other studies, the results presented herein indicate that transcriptional regulation of gonococcal genes by MtrR is centrally involved in determining levels of gonococcal susceptibility to penicillin and provides a framework for understanding how resistance developed over the years.