Macrolides bind reversibly to the 50S subunit of 70S bacterial ribosomes, which inhibits protein synthesis [293, 295]. Although macrolides are effective for other bacterial infections, including some mycobacteria, they have not demonstrated significant efficacy against MTb [293, 294]. Ribosome methylation is the most

R9 = oxime essential for activity; Increased lipophilicity increases both activity and toxicity

R11, Ri2 = carbamate or

Activity strongly depends upon R6

carbazate increases potency but / h C strongly inhibits CYP3A / 3 '

R2 = F more active and less toxic


Fig. 30 General SAR for macrolides (adapted from [293])


Result of CH3 acylation varies

Cladinose at C(3) gives good activity

widespread mechanism involved with macrolide resistance in MTb, and the gene ermMT plays an essential role [294-296]. Therefore, the current development goal for macrolides has been primarily to overcome bacterial resistances resulting from methylation of the rRNA and drug efflux [294, 295]. Furthermore, since macrolides are well-known inhibitors of CYP3A4, a cytochrome P450 enzyme, developing compounds with decreased inhibition against CYP3A4 is critical.

In addition to low efficacy against MTb, the pharmacokinetics of EM are somewhat unsatisfactory, as it is unstable to gastric acid and displays a short serum half-life (~1.4 h) [292, 293]. The second-generation macrolides such as clarithromycin and roxithromycin improved both properties [293], but clarithromycin showed only weak activity against MTb either in vitro or in vivo (200 mg/kg dose for low-dose aerosol infection mouse models), suggesting that second generation macrolides cannot be expected to offer significant antimicrobial clinical benefits for TB [293, 294]. Further improvements focused on replacement of the l-cladinose substituent, as it is associated with both drug efflux (one mechanism for development of macrolide resistance) and metabolic instability of the macro-lides [293]. This third generation of macrolides replaced the cladinose ring with a ketone moiety (ketolides), leading to more metabolically stable drugs [292-294]. However, it appears that C(3) cladinose is important for antitubercular potency of macrolides, which remain more potent than either ketolides or other substituents such as 3-OH and 3-carbamoyloxy groups [293, 294]. Telithromycin (Fig. 29; 20b), the first clinically approved ketolide, has been developed for use against respiratory pathogens but is not active against MTb [292-294].

Currently, there have been some improvements in in vitro activity with macro-lides against MTb, but to date no promising drug candidate has emerged. Preclinical work in this area is ongoing.

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