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  6. Christopher Davies, Ph.D.

Christopher Davies, Ph.D.

Physician name, Ph.D.Professor and Associate Dean for Research

Ph.D.: University of Bristol

cdavies@southalabama.edu

Research Interests

The primary interest of my laboratory is structure and function investigations of enzymes involved in peptidoglycan metabolism in bacteria. Much of our work to date has focused on penicillin-binding proteins (PBPs), starting with investigations of catalytic mechanism and then progressing to understanding mechanisms of antibiotic resistance. Our investigations have included PBPs from E. coli, M. tuberculosis, P. aeruginosa and N. gonorrhoeae. A major focus at present is to understand the impact of mutations in penicillin-binding protein 2 (PBP2) derived from cephalosporin-resistant strains of N. gonorrhoeae (including H041, identified in Japan, and F89, identified in France). Such strains signal a possible end to treatable gonorrhea and it is therefore important to elucidate the molecular mechanisms underlying antibiotic resistance. In particular, we seek to understand how mutations in PBP2 lower inhibition by cephalosporins without affecting the essential transpeptidase reaction with peptide substrate. The long-term goal is to employ this information for the design of new anti-gonococcal agents that overcome resistance mechanisms.

Toward that goal, we are increasingly engaged in drug discovery and development efforts targeting N. gonorrhoeae PBP2. Current efforts are directed toward testing and optimization of non-β-lactam PBP2 inhibitors identified through high-throughput screening against chemical and in silico libraries, and we are also working with a pharmaceutical company who are developing lead inhibitors of PBP2. 

Publications

  1. Fenton, B.A., Tomberg, J., Sciandra, C.A., Nicholas, R.A., Davies, C. & Zhou, P. (2021). Mutations in PBP2 from ceftriaxone-resistant Neisseria gonorrhoeae alter the dynamics of the β3-β4 loop to favor a low-affinity drug-binding state. J Biol Chem. 297: Oct; 297(4):101188. doi: 10.1016/j.jbc.2021.101188. PMCID: PMC8503634. 
  2. Singh, A., Izac, J.R., Schuler, E.J.A., Patel, D.T., Davies, C. & Marconi RT. (2021). High-resolution crystal structure of the Borreliella burgdorferi PlzA protein in complex with c-di-GMP: new insights into the interaction of c-di-GMP with the novel xPilZ domain. Pathog Dis. Jun 29;79(5). doi: 10.1093/femspd/ftab030. PMCID: PMC8240479. 
  3. Turner, J.M., Connolly, K.L., Aberman, K.E., Fonseca, J.C. 2nd, Singh, A., Jerse, A.E., Nicholas, R.A. & Davies, C. (2021) Molecular Features of Cephalosporins Important for Activity against Antimicrobial-Resistant Neisseria gonorrhoeae. ACS Infect Dis. Feb 12;7: 293-308. doi: 10.1021/acsinfecdis.0c00400. 
  4. Singh, A., Turner, J.M., Tomberg, J., Fedarovich, A., Unemo, M., Nicholas, R.A. & Davies, C. (2020). Mutations in penicillin-binding protein 2 from cephalosporin-resistant Neisseria gonorrhoeae hinder ceftriaxone acylation by restricting protein dynamics. J Biol Chem. 295:7529-7543. doi: 10.1074/jbc.RA120.012617. PMCID: PMC7247294. 
  5. Singh, A., Tomberg, J., Nicholas, R.A. & Davies, C. (2019). Recognition of the β-lactam carboxylate triggers acylation of Neisseria gonorrhoeae penicillin-binding protein 2. J Biol Chem. 294: 14020-14032. doi: 10.1074/jbc.RA119.009942. PMCID: PMC6755799. 
  6. Johnsen, U., Reinhardt, A., Landan, G., Tria, F.D.K., Turner, J.M., Davies, C. & Schönheit, P. (2019). New views on an old enzyme: allosteric regulation and evolution of archaeal pyruvate kinases. FEBS J. 286: 2471-2489. doi: 10.1111/febs.14837. 
  7. Young, B.F., Roth, B.M. & Davies, C. (2019). 1H, 13C, and 15N resonance assignments of N-acetylmuramyl-L-alanine amidase (AmiC) N-terminal domain (NTD) from Neisseria gonorrhoeae. Biomol NMR Assign. 13: 63-66. doi: 10.1007/s12104-018-9852-1. PMCID: PMC6440844.