How gonorrhea develops resistance to antibiotics
Steadily and relentlessly, the bacterium that causes gonorrhea has slipped past medicine's defenses, acquiring resistance to once-reliable drugs, including penicillin, tetracycline, and ciprofloxacin. These former stalwarts are no longer used to treat the sexually transmitted disease.
In 2010, after some strains of Neisseria gonorrhoeae, the bacterium responsible for gonorrhea, began showing resistance to one of the last remaining classes of antibiotics, the Centers for Disease Control and Prevention began recommending "dual therapy," meaning that doctors now prescribe two drugs at the same time to fight gonorrhea. Currently, those two drugs are ceftriaxone, a member of the cephalosporin class of antibiotics, and azithromycin.
With fears increasing that gonorrhea could breach these last defenses, the work of researchers like crystallographer Christopher Davies, Ph.D., is crucial.
"We're looking at a molecular level at the events that have got everybody worried out there in the clinics," said Davies, a professor in the Department of Biochemistry & Molecular Biology and director of the MUSC Center for Structural Biology.
Davies' team has just published a paper showing how cephalosporins bind and inactivate a gonococcal protein dubbed penicillin-binding protein 2 (PBP2). Led by postdoctoral fellow Avinash Singh, Ph.D., the researchers showed the protein undergoes key structural changes, including twisting and rolling of a loop to bind the antibiotic, that enhance the reaction with cephalosporins. Without these changes, the protein would react much more slowly with the antibiotic.
Davies explained that all antibiotics work by targeting essential functions in a particular bug. Cephalosporins work by attacking the bacterial cell wall.
Normally, PBP2 moves along the bacterial cell's cytoplasmic membrane, reaching out into the space between the cytoplasmic membrane and the outer membrane, looking for peptides to bind to. The protein joins peptides together to create a mesh -- just like an onion bag at the grocery store, Davies said. But antibiotics jump in to bind to the protein before it can get to a peptide.
"The protein is walking around the membrane layer as normal, but its active site is blocked by antibiotic, so all those potential interactions with the peptide substrate are fruitless," Davies said.
With the protein out of commission and not building the mesh, holes start to appear in the cell wall. Cytoplasm starts to leak out, and the cell bursts and dies, Davies said.
Yet the resistant strains, which have been identified in Japan, France, Spain and most recently in Canada, evade the lethal action of cephalosporins by preventing the antibiotic from binding to the protein target. How they achieve this is a major focus of Davies' research.