Discovery of MBL-AB01: a novel antibacterial xanthone antibiotic with high activity against methicillin-resistant <i>Staphylococcus aureus</i>

A novel compound denoted MBL-AB01 was isolated from a marine <i>Actinoalloteichus</i>, which belongs to a rare and underexplored class of <i>Actinobacteria</i>. This work demonstrates that the novel compound MBL-AB01 shows very high activity <i>in vitro</i> against six methicillin-resistant <i>Staphylococcus aureus</i> strains, and high activity against a panel of three other Gram-positive strains, including a vancomycin-resistant <i>Enterococcus faecium</i>. Structure elucidation of the compound revealed that MBL-AB01 is a polycyclic xanthone antibiotic closely related to the bioactive compounds: xantholipin and lysolipin. This class of antibiotics has caught interest due to its unique chemical structure and diverse biological activity. The gene cluster encoding MBL-AB01 production was identified, and the individual genes within the cluster were annotated along with proposed functional roles. The compound was produced by bioreactor fermentations, and significantly higher yields of MBL-AB01 were obtained after classical mutagenesis and fermentation process improvements.IMPORTANCEMethicillin-resistant <i>Staphylococcus aureus</i> (MRSA) infections have become a great challenge in hospitals over the last decades, and MRSA is currently one of the six pathogens on the World Health Organization priority list. Here, we demonstrate that the novel antibiotic MBL-AB01 has excellent antibacterial properties against six <i>S. aureus</i> strains, including MRSA. MBL-AB01 belongs to the poorly explored class of polycyclic xanthones, thereby fulfilling innovation criteria for the development of new antibiotics. The compound can be produced in sufficient amounts for early formulation development and pre-clinical trials.