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Dynamic time-kill curve characterization of spectinamide antibiotics 1445 and 1599 for the treatment of tuberculosis

2018; Elsevier BV; Volume: 127; Linguagem: Inglês

10.1016/j.ejps.2018.11.006

1879-0720

Pavan Vaddady, Ashit Trivedi, Chetan Rathi, Dora B. Madhura, Jiuyu Liu, Richard Lee, Bernd Meibohm,

Antibiotic Resistance in Bacteria

Spectinamides are a novel class of antibiotics under development for the treatment of MDR- and XDR-tuberculosis, with 1599 and 1445 as early lead candidates within this group. In order to evaluate and differentiate the pharmacological properties of these compounds and assist in candidate selection and design of optimal dosing regimens in animal models of Mtb infection, time kill curve assessments were performed in a previously established in vitro PK/PD model system. The performed studies and subsequent pharmacometric analysis indicate that the anti-mycobacterial activity of 1599 exhibits concentration-dependent killing whereas 1445 shows time-dependent killing. These findings are supported by the fact that the PKPD index that best describes bacterial killing is T > MIC for 1445, but fCmax/AUC for 1599. The differential killing behavior among the lead candidates can be rationalized by the differences in post-antibiotic effect: 15.7 h for 1445 compared the 133 h for 1599. Overall, the PK/PD based analysis of the in vitro pharmacologic killing profile of spectinamides 1599 and 1445 on mycobacteria provided valuable insights that contributed to lead candidate selection and preclinical development of these compounds.