Mechanisms of zidovudine resistance in bacteria

Abstract

Summary. Unlike their parent strains, zidovudine-resistant derivatives of Escherichia coli KL16 and Salmonella typhimurium NCTC 5710 were found to be incapable of incorporating radiolabelled thymidine into their chromosomal DNA. Since incorporation was still prevented in the presence of EDTA, resistance to zidovudine was not associated with a permeability barrier, but appeared to result from the loss of thymidine kinase activity, required for the phosphorylation of zidovudine. Pseudomonas aeruginosa, which is intrinsically zidovudine-resistant, was also shown to be incapable of incorporating thymidine into its DNA, but Staphylococcus epidermidis SK360 and Staph. aureus E3T, which are also intrinsically zidovudine-resistant, possessed thymidine kinase activity. This suggests that two distinct mechanisms of resistance to zidovudine exist in bacteria. Zidovudine resistance did not appear to confer resistance to other antibacterial agents.

Intracellular activity of zidovudine (3'-azido-3'-deoxythymidine, AZT) against Salmonella typhimurium in the macrophage cell line J774-2

“…The absence of thymidine kinase activity is observed with P. aeruginosa and Listeria species that are naturally resistant to AZT. However, this resistance is not transferable (9,10).…”

“…AZTresistant bacteria have been isolated from the stools of HIV patients receiving AZT (12). The mechanism of AZT resistance in enterobacteria is due to the loss of thymidine kinase activity (9). The absence of thymidine kinase activity is observed with P. aeruginosa and Listeria species that are naturally resistant to AZT.…”

In vitro activities of nucleoside analog antiviral agents against salmonellae

“…Salmonella and E. coli isolates obtained from ZDV-naive patients have previously been shown to be susceptible to ZDV in vitro (24,31). We and others (11,21,22) have been able to induce resistance in Salmonella species to ZDV in vitro. ZDV-resistant E. coli organisms have been detected in ZDV-treated mice with E. coli pyelonephritis (17).…”

“…Recently, ZDV-resistant E. coli and Salmonella isolates have been recovered from patients treated with ZDV (24,31). Acquired ZDV resistance of salmonellae and E. coli has been shown to result from loss of thymidine kinase activity (11,21,22,24). We were also able to induce resistance in Salmonella isolates in vitro to ddM.…”

“…After the observation that ZDV and ddI were active against Salmonella species, we determined the effect of the Salmonella and E. coli inoculum size on antibacterial activity. We also sought to extend previous observations regarding bacterial resistance to ZDV (17,21,22,24,31) or equal to 5 x 104 CFU/ml, but none of the isolates were inhibited when the inoculum size was S x 106 CFU/ml or larger (Fig. 2).…”