Hourigan David, Field Des, Murray Ellen, Sugrue Ivan, O'Connor Paula M, Hill Colin, Ross R Paul
APC Microbiome Ireland, Biosciences Institute, Biosciences Research Institute, University College, Cork, Ireland.
School of Microbiology, University College Cork, University College, Cork, Ireland.
mBio. 2025 Oct 8;16(10):e0154525. doi: 10.1128/mbio.01545-25. Epub 2025 Sep 10.
Bacteriocins are antimicrobial peptides/proteins that can have narrow or broad inhibitory spectra and remarkable potency against clinically relevant pathogens. One such bacteriocin that is extensively used in the food industry and with potential for biotherapeutic application is the post-translationally modified peptide, nisin. Recent studies have shown the impact of nisin on the gastrointestinal microbiome, but relatively little is known of how abundant nisin production is in nature, the breadth of existing variants, and their antimicrobial potency. Whether or not nisin production and immunity are widespread in gut microbiomes could be a deciding factor in determining the suitability of nisin as a prospective therapeutic for human and/or animal infections. Here, we used publicly available data sets to determine the presence of widespread and diverse nisin biosynthetic gene clusters (nBGCs) across the biosphere. We show that 30% of these nBGCs are predicted to be located on mobile genetic elements, with some found in pathogenic bacteria. Furthermore, we highlight evidence of horizontal gene transfer of nBGCs between genera, including , , and . In all, we describe 107 novel nisin-like peptides. Five representatives were heterologously expressed and all exhibited antimicrobial activity. We further characterized nisin VP, a novel natural nisin variant produced by isolated from the porcine gut. The peptide has a completely novel hinge region "AIQ" not detected in other nisin variants to date. While nisin VP could be induced by nisin A, the latter could not be induced by nisin VP.IMPORTANCEOur research reveals the heretofore underappreciated presence of diverse and widespread nisin-like biosynthetic gene clusters in microbiomes across the globe. Notably, different clusters share similar biosynthetic machinery but differ in sequence, suggesting gene transfer and adaptation. We identify >100 new nisin-like variants, including several in species not previously known to produce nisin. This emphasizes the widespread dissemination of nisin-like gene clusters and the diversity of novel core peptides with biotherapeutic potential. These findings point to a role for nisin in microbial competition in microbiomes. We heterologously expressed nine nisin variants, five of which are completely novel peptides, using the nisin A biosynthetic machinery and confirmed that all exhibited antimicrobial activity.
细菌素是一类抗菌肽/蛋白质，其抑菌谱可窄可宽，对临床相关病原体具有显著的抑制效力。在食品工业中广泛使用且具有生物治疗应用潜力的一种细菌素是翻译后修饰的肽——乳酸链球菌素。最近的研究表明了乳酸链球菌素对胃肠道微生物群的影响，但对于自然界中乳酸链球菌素的产量有多高、现有变体的广度及其抗菌效力却知之甚少。乳酸链球菌素的产生和免疫在肠道微生物群中是否普遍存在，可能是决定乳酸链球菌素作为人类和/或动物感染的潜在治疗剂是否合适的一个决定性因素。在这里，我们利用公开可用的数据集来确定全球生物圈中广泛存在且多样的乳酸链球菌素生物合成基因簇（nBGCs）的存在情况。我们发现，这些nBGCs中有30%预计位于可移动遗传元件上，其中一些存在于病原菌中。此外，我们强调了nBGCs在不同属之间水平基因转移的证据，包括[具体属名1]、[具体属名2]和[具体属名3]。总之，我们描述了107种新型乳酸链球菌素样肽。其中五个代表被异源表达，并且都表现出抗菌活性。我们进一步对乳酸链球菌素VP进行了表征，它是从猪肠道中分离出的[具体菌株名称]产生的一种新型天然乳酸链球菌素变体。该肽具有一个全新的铰链区“AIQ”，迄今为止在其他乳酸链球菌素变体中尚未检测到。虽然乳酸链球菌素VP可被乳酸链球菌素A诱导，但后者不能被乳酸链球菌素VP诱导。
我们的研究揭示了全球微生物群中迄今未被充分认识的多样且广泛存在的乳酸链球菌素样生物合成基因簇的存在。值得注意的是，不同的基因簇共享相似的生物合成机制，但序列不同，这表明存在基因转移和适应性变化。我们鉴定出100多种新的乳酸链球菌素样变体，包括一些来自以前未知会产生乳酸链球菌素的物种。这强调了乳酸链球菌素样基因簇的广泛传播以及具有生物治疗潜力的新型核心肽的多样性。这些发现表明乳酸链球菌素在微生物群中的微生物竞争中发挥作用。我们利用乳酸链球菌素A生物合成机制异源表达了九种乳酸链球菌素变体，其中五种是全新的肽，并证实它们都表现出抗菌活性。
