Staphylococcal antimicrobial biosynthetic gene clusters and their impact on bacterial fitness

The human nasal microbiome comprises a distinct community of bacterial species and its composition is strongly influenced by microbe-microbe and microbe-host interactions. To overcome competitors and to finally achieve niche occupation, bacteria can produce antimicrobial compounds like bacteriocins inhibiting competing bacteria in the vicinity of the producer cell. Recent studies could demonstrate that biosynthetic gene clusters encoding secondary metabolites like bacteriocins are frequently found in staphylococci isolated from the human nasal microbiome. Furthermore, these gene clusters show strong signs of mobility mediated by horizontal gene transfer, due to their localisation on plasmids or mobile genetic elements. Thus, horizontal gene transfer allows bacteria to rapidly acquire bacteriocin biosynthetic gene clusters to either remain or invade new ecological niches. However, the metabolic costs which are associated with sudden bacteriocin production are barely studied. Here, we describe the mechanism of secretion and producer immunity of the microbiome-derived antimicrobial lugdunin, report about another novel antimicrobial compound produced by a human nasal Staphylococcus epidermidis isolate, called epifadin, and we describe that horizontal gene transfer of micrococcin P1 negatively effects bacterial fitness and central metabolism, which can be bypassed by adaptive mutation. We demonstrate that secretion of and self-resistance to lugdunin, the first fibupeptide antibiotic isolated from the human nasal microbiome, is achieved by two distinct ABC transporters, which are encoded in the lugdunin operon. Our study could show the distinct but also overlapping roles of the two transporters and that both are required for full level lugdunin resistance. Epifadin is the first example of a staphylococcal bacteriocin produced by both, non-ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS). It shows activity against a broad spectrum of major nasal microbiome members despite its very short half-life, making epifadin a very unusual antimicrobial molecule. Furthermore, we report that horizontal gene transfer of the biosynthetic gene cluster encoding the thiopeptide micrococcin P1 in the lab strain Staphylococcus aureus RN4220 leads to a growth defect and disturbances of the cellular metabolism in the new host. Thus, we could demonstrate that sudden bacteriocin production is a burden for the new producer, which can be, however, reverted by adaptive mutation in citZ, encoding the citrate synthase, turning micrococcin P1 production into a benefit. Our findings highlight the frequent occurrence and high mobility of bacteriocin biosynthetic gene clusters in the human nasal microbiome and the costs and benefits which are associated with acquisition of these gene clusters.Die Dissertation ist bis zum 02. September 2024 gesperrt