In this study, Mankin, Wilson, Wright and colleagues used improved fractionation approaches and discovered a new antibiotic with a previously unknown mode of action.
The authors went on to show that MKM has a new chemical scaffold, and they identified and characterized the putative biosynthetic gene clusters responsible for its production.
Moreover, the compound did not permeabilize or disrupt the bacterial membrane and the authors did not detect any changes in bacterial cell morphology, which suggests an intracellular target.
Indeed, the authors were able to show that MKM interferes with bacterial growth by inhibiting the ribosome.
In sum, this study reports the identification of an antibacterial compound with a novel scaffold and a new site of action on the bacterial ribosome, with promising potential for further antibiotic development.
Actinomycetes produce a myriad of natural products and have been an important source of clinically used antibiotics. The genus Streptomyces harbours an abundance of biosynthetic gene clusters that could encode antibacterial compounds. Despite great efforts, drug discovery approaches have led to the rediscovery of known drug scaffolds. In this study, Mankin, Wilson, Wright and colleagues used improved fractionation approaches and discovered a new antibiotic with a previously unknown mode of action. The authors fractionated a library of natural product extracts from soil bacteria and screened them for growth inhibitory activity, which has led to the discovery of a previously unknown cyclic depsipeptide produced by Streptomyces rimosus that they termed manikomycin (MKM). The authors went on to show that MKM has a new chemical scaffold, and they identified and characterized the putative biosynthetic gene clusters responsible for its production. Moreover, the compound did not permeabilize or disrupt the bacterial membrane and the authors did not detect any changes in bacterial cell morphology, which suggests an intracellular target. Indeed, the authors were able to show that MKM interferes with bacterial growth by inhibiting the ribosome. Specifically, MKMs bind to the E-site of the large subunit of the bacterial ribosome, preventing entry of the 3ʹ end of the transfer RNA into the E-site and thus interfering with translocation, which is a unique mechanism of action. In addition, the authors showed that MKM exhibits selective antimicrobial activity against the Gram-negative Enterobacteriaceae Escherichia coli and Klebsiella pneumoniae, and also inhibits the growth of Mycobacterium species. Finally, MKM is not susceptible to ribosome-based resistance mechanisms found in clinical isolates.
In sum, this study reports the identification of an antibacterial compound with a novel scaffold and a new site of action on the bacterial ribosome, with promising potential for further antibiotic development.
