Secondary metabolites governing staphylococcal survival in the nasal microbiome

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Dokumentart: Dissertation
Date: 2023-10-20
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Peschel, Andreas (Prof. Dr.)
Day of Oral Examination: 2021-10-28
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
Keywords: Staphylococcus , Staphylococcus aureus , Staphylococcus epidermidis
Other Keywords:
Secondary metabolites
Antimicrobial molecules
Nasal microbiome
License: Publishing license including print on demand
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Dissertation ist gesperrt bis zum 20.10.2023 !!


Staphylococcus species are amongst the ubiquitous members of the human microbiome and generally populate human epithelial surfaces such as the skin and nose. The nare microbiomes of ~30% of the human population include the frequently multidrug-resistant facultative pathogen Staphylococcus aureus, which can cause a broad range of often severe infections. Although S. aureus nasal colonization is linked to an enhanced risk of endogenous S. aureus infections, the reasons for why only a subset of the human population is colonized have remained largely unknown. Increasing evidence points to important roles of bacterial secondary metabolites, in particular antimicrobial compounds, in shaping microbiome composition and dynamics, and, hence, in pathogen exclusion. Here, we report a novel antimicrobial compound produced by the human nasal isolate Staphylococcus epidermidis IVK83, epifadin, describe how mutualistic nasal bacteria promote nasal colonization by S. lugdunensis, the producer of the recently published microbiome-derived antimicrobial lugdunin, and elucidate the mechanisms of lugdunin secretion and producer immunity. Epifadin is the first example of a staphylococcal bacteriocin produced by both, non-ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS). It is active against a broad spectrum of major nasal microbiome members and enables S. epidermidis to outcompete S. aureus in vitro and in vivo. Interestingly, epifadin exhibits a very short half-life, thereby presumably preventing collateral damage of mutualistic bacteria. The unprecedented molecular architecture and instability render epifadin a novel and unusual antimicrobial. We demonstrate that lugdunin secretion and self-resistance are mediated by two ABC transporters, which are encoded within the lugdunin locus. They display distinct but overlapping functions and are both required for full level lugdunin resistance. Furthermore, we show that nasal carriage of S. lugdunensis is linked to a significantly decreased S. aureus colonization rate in healthy volunteers, as previously observed in hospitalized patients. A long-term analysis of S. lugdunensis carriers revealed that nasal colonization by S. lugdunensis is rather stable and mainly associated with microbiomes dominated by other Staphylococcus and/or by Corynebacterium species. Some of these bacteria promote S. lugdunensis growth via the production of iron-scavenging siderophores, indicating mutualistic interactions. Our findings demonstrate the potential of secondary metabolites in modulating interbacterial interactions. Further investigations will help us understand their real impact in shaping microbiome composition.

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