The skin microbiota is thought to play a key role in host protection from infection. Nisin J is a novel nisin variant produced by Staphylococcus capitis APC 2923, a strain isolated from the toe web space area in a screening study performed on the human skin microbiota. Whole-genome sequencing and mass spectrometry of the purified peptide confirmed that S. capitis APC 2923 produces a 3,458-Da bacteriocin, designated nisin J, which exhibited antimicrobial activity against a range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and Cutibacterium acnes. The gene order in the nisin J gene cluster (nsjFEGBTCJP) differs from that of other nisin variants in that it is lacking the nisin regulatory genes, nisRK, as well as the nisin immunity gene nisI. Nisin J has 9 amino acid changes compared to prototypical nisin A, with 8 amino acid substitutions, 6 of which are not present in other nisin variants (Ile4Lys, Met17Gln, Gly18Thr, Asn20Phe, Met21Ala, Ile30Gly, Val33His, and Lys34Thr), and an extra amino acid close to the C terminus, rendering nisin J the only nisin variant to contain 35 amino acids. This is the first report of a nisin variant produced by a Staphylococcus species and the first nisin producer isolated from human skin. IMPORTANCE This study describes the characterization of nisin J, the first example of a natural nisin variant, produced by a human skin isolate of staphylococcal origin. Nisin J displays inhibitory activity against a wide range of bacterial targets, including MRSA. This work demonstrates the potential of human commensals as a source for novel antimicrobials that could form part of the solution to antibiotic resistance across a broad range of bacterial pathogens.

Nisin A is the most extensively studied lantibiotic and has been used as a preservative by the food industry since 1953. This 34 amino acid peptide contains three dehydrated amino acids and five thioether rings. These rings, resulting from one lanthionine and four methyllanthionine bridges, confer the peptide with its unique structure. Nisin A has two mechanisms of action, with the N-terminal domain of the peptide inhibiting cell wall synthesis through lipid II binding and the C-terminal domain responsible for pore-formation. The focus of this study is the three amino acid ‘hinge’ region (N 20, M 21 and K 22) which separates these two domains and allows for conformational flexibility. As all lantibiotics are gene encoded, novel variants can be generated through manipulation of the corresponding gene. A number of derivatives in which the hinge region was altered have previously been shown to possess enhanced antimicrobial activity. Here we take this approach further by employing simultaneous, indiscriminate site-saturation mutagenesis of all three hinge residues to create a novel bank of nisin derivative producers. Screening of this bank revealed that producers of peptides with hinge regions consisting of AAK, NAI and SLS displayed enhanced bioactivity against a variety of targets. These and other results suggested a preference for small, chiral amino acids within the hinge region, leading to the design and creation of producers of peptides with hinges consisting of AAA and SAA. These producers, and the corresponding peptides, exhibited enhanced bioactivity against Lactococcus lactis HP, Streptococcus agalactiae ATCC 13813, Mycobacterium smegmatis MC2155 and Staphylococcus aureus RF122 and thus represent the first example of nisin derivatives that possess enhanced activity as a consequence of rational design.

In order for bacteria to survive and grow in a particular environment, they must be able to defend themselves against competing bacteria. To do this, many produce antimicrobial compounds which kill their competitors without harming themselves. Bacteriocins are an excellent example of bacterially produced antimicrobials. Bacteriocins produced by lactic acid bacteria, which are safe bacteria found in milk, cheese and a variety of fermented foods, are the focal point of this research. Nisin is by far the most researched of all bacteriocins. Its first use as a food preservative was in 1953 and its use has been approved in 48 counties worldwide. After nisin, lacticin 3147 is one of the most thoroughly researched bacteriocins. The bacterial strain that produced lacticin 3147 was found in Ireland and lacticin 3147 is an Irish-owned bacteriocin. Although there are today a number of other bacteriocins available, nisin and lacticin 3147 are the primary interests ...

Since the 1925 discovery that strains of Escherichia coli can retard the growth of neighbouring bacteria, the study of bacteriocins has continuously evolved. During the intervening period, a large and heterogeneous collection of these antimicrobial peptides has been isolated from a myriad of sources and numerous investigations have been carried out with a view to harnessing their potency. The most thoroughly investigated class of bacteriocins, the lantibiotics, is the main focus of this review. These antimicrobial peptides inhibit many human and animal pathogens. They have been the focus of considerable efforts to maximize the potential of existing lantibiotics, identify new and better lantibiotics from nature and utilize bioengineering-based approaches to further improve upon existing well-characterized compounds.