Increasing bacterial resistance to antibiotics is making infections, especially those acquired in medical care settings, harder to treat. Under the direction of George Jacoby, MD, the Lahey Hospital & Medical Center’s Infectious Disease lab has worked on the mechanisms of antibiotic resistance using the tools of bacterial genetics and biochemistry. The hope is that such knowledge will speed treatment of infections with effective antibiotics and facilitate the discovery of new and better antimicrobial agents.
For many years the Infectious Disease lab has worked on β-lactamases, the enzymes that allow bacteria to inactivate penicillins, cephalosporins, carbapenems, and related antibiotics. The lab still maintains a web site to which investigators can submit potentially novel β-lactamase sequences for validation and naming (http://www.lahey.org/studies/).
Over the past dozen years, this lab has switched to work on bacterial resistance to fluoroquinolones, agents like levofloxacin and ciprofloxacin that kill bacteria by targeting the essential enzymes that twist and untwist DNA as it is replicated and expressed. Mutations in these enzymes can provide quinolone resistance. They discovered that quinolone resistance was also carried by plasmids, small circles of DNA that can be transferred between bacteria, spreading resistance. They purified the responsible protein, named it Qnr, showed that Qnr could protect the target enzymes from quinolone inhibition, and that Qnr protein had a rod-like shape and surface charge mimicking DNA. Qnr genes have been found on plasmids all over the world and also on the chromosome of many bacteria, including samples from the Lahey Microbiology lab. The lab is still studying how Qnr acts, where the qnr gene is found in nature, and what role it played before quinolones were discovered.
Martínez-Martínez L, Pascual A, Jacoby G. Quinolone resistance from a transferable plasmid. Lancet 1998; 351:797-9.
Tran JH, Jacoby GA. Mechanism of plasmid-mediated quinolone resistance. Proc Natl Acad Sci USA 2002; 99:5638-42.
Jacoby GA, Munoz-Price LS. The new ß-lactamases. N Engl J Med 2005; 352:380-91.
Strahilevitz J, Jacoby GA, Hooper DC, Robicsek A. Plasmid mediated quinolone resistance: a multifaceted threat. Clin. Microbiol. Rev. 2009; 22:664-89.
Vetting MW, Hegde SS, Wang M, Jacoby GA, Hooper DC, Blanchard JS. Structure of QnrB1, a plasmid-mediated fluoroquinolone resistance factor. J. Biol. Chem 2011 286: 25265-73.