Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains

Abstract

The spread of multiresistant bacteria increases the need for new antibiotics. The observation that some nucleoside analogues have antibacterial activity led us to further investigate the antimicrobial activity and resistance of zidovudine (AZT). We determined the minimum inhibition concentration (MIC), studied time-kill curves, induced resistant bacteria and sequenced the gene for thymidine kinase. We demonstrate that AZT has a bactericidal effect on some enterobacteria. However, AZT could induce resistance in Escherichia coli. These resistances were associated with various modifications in the thymidine kinase gene. In particular, we observed the presence in this gene of an insertion sequence (IS) similar to IS911 of Shigella dysenteriae in two resistant clones. No cross-resistance with classical antibiotics in strains with modified thymidine kinase gene was observed. Finally, an additive or synergistic activity between AZT and the two aminoglycoside antibiotics amikacin and gentamicin was observed. We demonstrate the bactericidal activity of AZT and show synergy in association with gentamicin. Genetic modifications in resistant bacteria were identified. Our results indicate that AZT could potentially be added in the treatment of infections with enterobacteria or represent the basis for the development of derivatives with better activity and inducing less resistance.

Gemcitabine is active against clinical multiresistant Staphylococcus aureus strains and is synergistic with gentamicin

“…No gene was totally deleted from the genome in any of the resistant strains. Several strains had point mutations inducing modifications in protein sequences of A36T T42G A51T C89T T143C T152A T154A C198T T200C T211C T234A -I14M -A30V L48S F51Y Y52N -L67S F71L F78L T78A T80A -27 STOP T25C A46C T54C R9W S16R - SadAK, consistent with our previous observations in zidovudineresistant Escherichia coli and gemcitabine-resistant human cancer cells [6,11]. However, there was no correlation between MICs of resistant strains and the sequence of SadAK, except for the absence of premature stop codon in strains with relatively low MICs (16-32× MIC).…”

“…1). Again, and as demonstrated with zidovudine, this result confirms that nucleoside analogues could have their place in microbiology [6].…”

“…Based on these previously published data as well as our expertise in the field of nucleoside analogues, we have developed a strategy to identify nucleoside analogues as new antibiotics. We recently reported on further investigation of the antibacterial activity of zidovudine, its possible use in association with other drugs, and its mechanisms of resistance [6]. In a similar way, based on reports from Sandrini et al [4,5], we believe that gemcitabine is a good candidate for drug repositioning into infectious diseases, particularly in the hospital setting.…”

Serum bactericidal activity of colistin and azidothymidine combinations against mcr-1-positive colistin-resistant Escherichia coli

“…AZT acts antibacterial against Enterobacteriaceae [8]. Furthermore, a synergistic antibacterial activity between AZT and gentamicin or colistin was shown for Enterobacteriaceae strains recently [9,Hu et al submitted,unpublished data].…”

3‐Aryl‐4‐methyl‐2‐quinolones Targeting Multiresistant Staphylococcus aureus Bacteria

“…[1][2][3][4][5][6] In the Staphylococcus aureus genome (2.8 Mb), approximately 253 open reading frames (ORFs) have been described as encoding putative transport pumps. This phenomenon, which was first discovered in 1980 with the transport of tetracyclines out of the enterobacteria, is due to numerous efflux systems described both in Gram-negative and Gram-positive bacteria.…”