Emergence of plasmid-mediated antibiotic resistance in Yersinia pestis

Plague is not anymore the threatening disease that killed millions of human beings during the past centuries. Public health measures and effective therapy led to a drastic decrease of the disease worldwide. However, plague has never been eradicated. Since the beginning of the 90s, the number of human cases is constantly rising and plague outbreaks are reappearing in various countries after decades of silence. Plague is therefore categorized as a reemerging disease. Until recently, Yersinia pestis was considered as susceptible to all antibiotics classically used to treat infections due to Gram-negative bacteria. In 1995, a Y. pestis strain resistant to most of the drugs recommended for plague prophylaxis and therapy was isolated in Madagascar from a 16-year old patient with symptoms of bubonic plague. This strain was highly resistant to ampicillin, chloramphenicol, kanamycin, streptomycin-spectinomycin, sulfonamide, and tetracycline-minocycline. Despite lack of synergism between sulfonamide and sulfamethoxazole, the patient was successfully treated with co-trimoxazole. Resistance was mediated by a 150 kb Inc6-C self-transferable plasmid that could conjugate to other strains of Y. pestis and to E. coli at high frequencies (ca. 10(-2)). The resistance genes were homologous to plasmid-borne determinants commonly found in Enterobacteriaceae, suggesting that the multiresistant plasmid was acquired from a member of this family. Another Y. pestis strain with high-level resistance to streptomycin was isolated again in Madagascar in 1995 from a 14-year-old patient presented with bubonic plague. Resistance was carried by a 40-kb plasmid which was self-transferable at high frequencies to Y. pestis and Y. pseudotuberculosis and at a lower frequency to E. coli. These two observations of acquisition by Y. pestis of resistance plasmids under natural conditions indicates the emergence of drug resistance in this bacterial species highly pathogenic for humans.