title: In vitro antimycobacterial activity of newly synthesised S-alkylisothiosemicarbazone derivatives and synergistic interactions in combination with rifamycins against Mycobacterium avium.
abstract: The antimycobacterial activities of two new S-alkylisothiosemicarbazone derivatives (1i and 1f) against 32 Mycobacterium avium isolates were investigated. The minimum inhibitory concentrations (MICs) were significantly lower than those of rifampicin and other reference drugs. The two derivatives also showed excellent intracellular activity against M. avium residing in the macrophage-like J774 cells. Interestingly, the combination of subinhibitory concentrations of 1i and rifabutin or rifampicin induced a potent synergistic effect, as determined by the fractional inhibitory concentration indexes (FICIs) ranging between 0.103 and 0.412. Such synergistic effect resulted in a 81-fold and 139-fold reduction of the MICs of rifabutin and rifampicin, respectively. Enhancement of intracellular activity of rifabutin by the S-alkylisothiosemicarbazone derivative 1i was also observed. Results indicate that S-alkylisothiosemicarbazones can be useful in the therapy and prophylaxis of M. avium infections and can represent a template for the development of novel antimycobacterial drugs. Furthermore, as a consequence of their ability to enhance the activity of rifamycins, a reduction of drug interactions following the co-administration of protease inhibitors could be achieved by lower doses of rifampicin and rifabutin.
authors.affiliation: Division of Medical Microbiology, Department of Biomedical Sciences and Technologies, University of Cagliari, Viale Sant'Ignazio 38, 09123 Cagliari, Italy. adelogu@unica.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Logu
authors.forename: Manuela
authors.initials: M
authors.lastname: Saddi
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.forename: Clara
authors.initials: C
authors.lastname: Sanna
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.forename: Rita
authors.initials: R
authors.lastname: Borgna
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Cocco
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D012294:Rifamycins / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D012294:Rifamycins; D013882:Thiosemicarbazones