MBX-1066

The prevalence of drug-resistant bacteria in the clinic has propelled a concerted effort to find new classes of antibiotics that will circumvent current modes of resistance. We have previously described a set of bisamidine antibiotics that contains a core composed of two indoles and a central linker. The first compounds of the series, MBX 1066 and MBX 1090, have potent antibacterial properties against a wide range of Gram-positive and Gram-negative bacteria. We have conducted a systematic exploration of the amidine functionalities, the central linker, and substituents at the indole 3-position to determine the factors involved in potent antibacterial activity. Some of the newly synthesized compounds have even more potent and broad-spectrum activity than MBX 1066 and MBX 1090.

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA)1 and multi/extensively drug-resistant Mycobacterium tubcerulosis is a major global health problem.We have shown that several members of the bis-imidazolinylindole compounds exhibit very potent in vitro activity against both susceptible and multidrug-resistant isolates of M. tuberculosis as well as in vivo activity against cMRSA.A newer analog, MBX 1162, demonstrated equivalent potency and slightly increased mammalian cell toxicity compared with MBX 1066.Optimization of the scaffold proceeds with the goal of lessening toxicity while maintaining potency.These compounds represent a promising new scaffold for the treatment of drug-resistant bacterial pathogens.