Other modifications of established antibiotics classes

Numerous additional reports of new antibiotic analogs have been published recently with notable examples cited here. While not strictly speaking 'antibacterial agents' p-lactamase inhibitors have found utility, particularly when paired with a specific antibiotic (e.g., Augmentin) [61]. The penem sulfone SA-2-13 11 was designed as a class A p-lactamase inhibitor using the crystal structure of tazobactam bound to the p-lactamase E166A SHV-1 as a guide. In tests, the trans-enamine intermediate formed by the SA-2-13 with sHV-1 was found to be 10 times more stable than the analogous tazobactam intermediate [62]. A new 6-alkylidenepenicillanic acid sulfone LN-1-255 12, a potent inhibitor of serine p-lactamases, was shown to dramatically lower the MICs of cefpirome and ceftazidime against highly resistant Enterobacteriaceae [63]. A novel non-p-lactam inhibitor NXL104 13 has been shown to irreversibly inhibit both class A and class C p-lactamases [64,65]. In experiments with highly resistant Enter-obacteriaceae, NXL104 restored rapid bactericidal activity to ceftazidime. NXL104 entered Phase I clinical trials in 2007.

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BAL19403 14 is a new macrolide that is highly potent against erythromycin-resistant and clindamycin-resistant propionibacteria [66,67]. Potent antiinflammatory activity and good pre-clinical safety make BAL19403 a good candidate for topical treatment of acne [68-70]. AR-709 15 is a new di-aminopyridine in Phase I clinical trials derived from a program aimed at optimizing dihydrofolate reductase (DHFR) inhibitors treating respiratory infections caused by multi-drug-resistant Streptococci, Pneumococci, and Staphylococci [71-73]. In enzyme assays using wild-type and mutant DHFR isolated from S. pneumoniae and S. aureus, the IC50 for AR-709 was 12 x-60 x lower than for trimethoprim (TMP) for the wild-type and 50-100 x lower for the mutant enzyme [74]. Accordingly, AR-709 has demonstrably more potent antibacterial activities than TMP against both TMP-S and TMP-R strains of S. pneumoniae and S. aureus. AR-709 is currently in a radiolabelled Human Microdose study where preliminary results indicate that the drug distributes well in the target lung tissue.

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