Bacteria that are normally resident in the body have many roles in supporting health. Researchers have now identified a bacterial resident of the nose that produces an antibiotic that is active against a pathogen. See Article p.511
There is immense clinical concern about the rise of antibiotic-resistant 'superbugs' — such as strains of the bacterium Staphylococcus aureus known as methicillin-resistant S. aureus (MRSA) that have developed resistance to several key antibiotics. Faced with the growth of resistant strains of bacteria, finding more antibiotics is an urgent necessity. Most antibiotics have been isolated from soil-living bacteria, but on page 511, Zipperer et al.1 identify an antibiotic produced by a bacterial resident of the human nose that is active against strains of MRSA.
Staphylococcus aureus is an opportunistic human pathogen and, in addition to causing MRSA infections, is responsible for many infections, including those of the bloodstream (bacteraemia) and the lining of the heart (endocarditis), or infections surrounding prosthetic implants. S. aureus is found in the noses of around 30% of the population. This has prompted efforts to decolonize the nose with various antibiotics2 — a controversial practice, considering efforts to reduce antibiotic use. But how is it that 70% of the population resist colonization by S. aureus?
The presence of several nasal bacteria, including other Staphylococcus species, is negatively correlated with the presence of S. aureus. But the mechanism that underlies this distribution pattern — and the presumed inhibition of S. aureus invasion (known as colonization resistance) — has been a mystery3. To investigate this potential bacterial antagonism, Zipperer and colleagues screened 90 Staphylococcus samples from the human nasal cavity, including many Staphylococcus species, to test for S. aureus growth inhibition.
One strain, Staphylococcus lugdunensis, cleared a growing population of S. aureus, suggesting that the strain secretes a compound that causes the breakdown (lysis) of S. aureus. Using a library of S. lugdunensis mutants in which individual genes had been knocked out, the researchers identified a single mutant that was unable to inhibit S. aureus. Studying this mutant enabled identification of the compound responsible for S. aureus inhibition — a peptide antibiotic that the authors named lugdunin. Zipperer and colleagues' findings suggest that treatment with S. lugdunensis (or use of lugdunin) may be a valuable tool for the prevention of S. aureus colonization in the clinic.
It may seem surprising that a member of the human microbiota — the community of bacteria that inhabits the body — produces an antibiotic. However, the microbiota is composed of more than a thousand species4, many of which compete for space and nutrients, and the selective pressure to eliminate bacterial neighbours is high. This intense competition can be observed by surveying patterns of bacterial communities in which the presence of a particular species is negatively associated with the presence of other species5.
One probable mechanism for these negative interactions is the production of antibiotics. Although conventional antibiotic discovery has focused on mining compounds from soil-living bacteria, genome-wide analysis of the human microbiome has identified many gene clusters that encode enzymes associated with antibiotic production, such as polyketide synthases or non-ribosomal peptide synthetases. However, only a few such antibiotics have been characterized in the laboratory: strain-specific bacterial inhibitory molecules called bacteriocins6,7; fairly large peptide antibiotics called lantibiotics8; and the antibiotic lactocillin, which is active against several pathogenic bacteria9. Until now, evidence linking these compounds to the competitive advantage that they may confer has been lacking. The current study fills this gap.
Zipperer and colleagues found that lugdunin is active against several pathogens, including MRSA strains and Enterococcus bacteria that are resistant to the antibiotic vancomycin — and the bacteria treated with lugdunin did not develop resistance to it. In both in vitro and in vivo studies in mice, the ability of S. lugdunensis to outcompete S. aureus depends on the presence of a functional lugdunin biosynthesis pathway.
When the authors analysed 187 hospitalized patients, they found that S. aureus colonization was just 5.9% in individuals who carry S. lugdunensis, compared with 34.7% in individuals without S. lugdunensis. When produced by a bacterium that occupies a confined niche, it is clear that lugdunin and similar antibiotics have considerable power to influence bacterial community structure. Given that S. lugdunensis is present in only around 10% of the population and S. aureus is found in about 30% of the population, there are probably more antibiotics yet to be discovered that are responsible for S. aureus colonization resistance.
Lugdunin was found to be effective as a topical agent (applied to the surface) for treating an S. aureus skin infection in mice. Considering that lugdunin can inhibit the synthesis of major biopolymers (proteins, DNA and peptidoglycans) in S. aureus, it is probably a membrane-acting antibiotic, which would be challenging to develop into a systemic therapeutic because such compounds also tend to disrupt membranes of mammalian cells.
The method of discovery of lugdunin reported by Zipperer and colleagues provides a general approach to investigating antibiotic-driven colonization resistance of the human microbiota against pathogens (Fig. 1). By combining genomic and co-occurrence data, bacteria can be identified that are negatively correlated with the presence of a pathogen and that have the potential to produce antibiotics. These organisms, or the antibiotics they produce, might serve as drug-discovery leads.
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