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PERSONAL WEBSITE:
https://www.med.unc.edu/pharm/directory/robert-a-nicholas-phd/ |
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The primary focus of my research is to elucidate at the molecular level the mechanisms of chromosomally mediated antibiotic resistance in N. gonorrhoeae. My laboratory utilizes a wide range of approaches, including genetics, molecular biology, bacteriology, structural biology, and biochemistry. We have established experimental systems that allow us to define the contributions of multiple resistance determinants to antibiotic resistance, to identify the mutations in each determinant that confer resistance, and to quantify the synergism between these determinants in the acquisition of resistance. We have identified the 8 most important mutations of over 60 total in mosaic Penicillin-Binding Protein 2 (PBP2; the main target of beta-lactam antibiotics in N. gonorrhoeae) from ceftriaxone-resistant strains, which has helped the field focus on surveillance and epidemiology to identify new outbreaks of antibiotic-resistant N. gonorrhoeae. Our structural studies with Dr. Christopher Davies at the Univ of South Alabama are focused on identifying the structural mechanisms by which mosaic PBP2 has remodeled its active site to discriminate against ceftriaxone, and spawned new research directions to discover beta-lactams that evade these resistance mechanisms. I am a member of a large U19 center (Gonococcal Vaccine Cooperative Research Center) working to identify vaccine candidates against N. gonorrhoeae. I also have active collaborations with Drs. Ann Jerse at Uniformed Services University and Yonatan Grad at Harvard University on the role of compensatory mutations in the development of antibiotic resistance, and with Dr. Alex Duncan at UNC investigating how the major outer membrane porin, PorB, inhibits antigen presentation and dendritic cell-mediated T cell proliferation, as part of a long-range goal to understand how N. gonorrhoeae evades the human immune system and also how to make outer membrane vesicle vaccines more effective.
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CLINICAL/RESEARCH INTERESTS:
Bacteriology, Biochemistry, Drug Discovery, Microbiology, Pathogenesis & Infection, Structural Biology |