Discovery and Biosynthesis of Imidazolium Antibiotics from the Probiotic <i>Bacillus licheniformis</i>
Song Lim Ham, Tae Hyun Lee, Kyung Jun Kim, Jung Ha Kim, Su Jung Hwang, Sun Ho Lee, Jae Sik Yu, Ki Hyun Kim, HJ Lee, Wonsik Lee, Chung Sub Kim
Abstract
Antibiotic resistance is one of the world’s most urgent public health problems, and novel antibiotics to kill drug-resistant bacteria are needed. Natural product-derived small molecules have been the major source of new antibiotics. Here we describe a family of antibacterial metabolites isolated from a probiotic bacterium, Bacillus licheniformis . A cross-streaking assay followed by activity-guided isolation yielded a novel antibacterial metabolite, bacillimidazole G, which possesses a rare imidazolium ring in the structure, showing MIC values of 0.7–2.6 μg/mL against human pathogenic Gram-positive and Gram-negative bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and a lipopolysaccharide (LPS)-lacking Acinetobacter baumannii Δ lpxC . Bacillimidazole G also lowered MICs of colistin, a Gram-negative antibiotic, up to 8-fold against wild-type Escherichia coli MG1655 and A. baumannii . We propose a biosynthetic pathway to the characterized metabolites based on precursor-feeding studies, a chemical biological approach, biomimetic total synthesis, and a biosynthetic gene knockout method.