Secretion of and Self-Resistance to the Novel Fibupeptide Antimicrobial Lugdunin by Distinct ABC Transporters in Staphylococcus lugdunensis.

Lugdunin is the first reported nonribosomally synthesized antibiotic from human microbiomes. Its production by the commensal Staphylococcus lugdunensis eliminates the pathogen Staphylococcus aureus from human nasal microbiomes. The cycloheptapeptide lugdunin is the founding member of the new class of fibupeptide antibiotics, which have a novel mode of action and represent promising new antimicrobial agents. How S. lugdunensis releases and achieves producer self-resistance to lugdunin has remained unknown. We report that two ABC transporters encoded upstream of the lugdunin-biosynthetic operon have distinct yet overlapping roles in lugdunin secretion and self-resistance. While deletion of the lugEF transporter genes abrogated most of the lugdunin secretion, the lugGH transporter genes had a dominant role in resistance. Yet all four genes were required for full-level lugdunin resistance. The small accessory putative membrane protein LugI further contributed to lugdunin release and resistance levels conferred by the ABC transporters. Whereas LugIEFGH also conferred resistance to lugdunin congeners with inverse structures or with amino acid exchange at position 6, they neither affected the susceptibility to a lugdunin variant with an exchange at position 2 nor to other cyclic peptide antimicrobials such as daptomycin or gramicidin S. The obvious selectivity of the resistance mechanism raises hopes that it will not confer cross-resistance to other antimicrobials or to optimized lugdunin derivatives to be used for the prevention and treatment of S. aureus infections.

Commensal production of a broad-spectrum and short-lived antimicrobial peptide polyene eliminates nasal Staphylococcus aureus.

Antagonistic bacterial interactions often rely on antimicrobial bacteriocins, which attack only a narrow range of target bacteria. However, antimicrobials with broader activity may be advantageous. Here we identify an antimicrobial called epifadin, which is produced by nasal Staphylococcus epidermidis IVK83. It has an unprecedented architecture consisting of a non-ribosomally synthesized peptide, a polyketide component and a terminal modified amino acid moiety. Epifadin combines a wide antimicrobial target spectrum with a short life span of only a few hours. It is highly unstable under in vivo-like conditions, potentially as a means to limit collateral damage of bacterial mutualists. However, Staphylococcus aureus is eliminated by epifadin-producing S. epidermidis during co-cultivation in vitro and in vivo, indicating that epifadin-producing commensals could help prevent nasal S. aureus carriage. These insights into a microbiome-derived, previously unknown antimicrobial compound class suggest that limiting the half-life of an antimicrobial may help to balance its beneficial and detrimental activities.

Secondary Metabolites Governing Microbiome Interaction of Staphylococcal Pathogens and Commensals.

Various Staphylococcus species colonize skin and upper airways of warm-blooded animals. They compete successfully with many other microorganisms under the hostile and nutrient-poor conditions of these habitats using mechanisms that we are only beginning to appreciate. Small-molecule mediators, whose biosynthesis requires complex enzymatic cascades, so-called secondary metabolites, have emerged as crucial components of staphylococcal microbiome interactions. Such mediators belong to a large variety of compound classes and several of them have attractive properties for future drug development. They include, for instance, bacteriocins such as lanthipeptides, thiopeptides, and fibupeptides that inhibit bacterial competitor species; signaling molecules such as thiolactone peptides that induce or inhibit sensory cascades in other bacteria; or metallophores such as staphyloferrins and staphylopine that scavenge scant transition metal ions. For some secondary metabolites such as the aureusimines, the exact function remains to be elucidated. How secondary metabolites shape the fitness of Staphylococcus species in the complex context of other microbial and host defense factors remains a challenging field of future research. A detailed understanding will help to harness staphylococcal secondary metabolites for excluding the pathogenic species Staphylococcus aureus from the nasal microbiomes of at-risk patients, and it will be instrumental for the development of advanced anti-infective interventions.