Dr hab. Tamara Aleksandrzak-Piekarczyk
Laboratory of Lactic Acid Bacteria
New trends in research on lactic acid bacteria (LAB)
Lactic acid bacteria (LAB) are low GC Gram-positive bacteria, acid-tolerant, usually nonsporulating, nonrespiring, rod-shaped (bacilli) or spherical (cocci) lactic acid-producing bacteria that share common metabolic and physiological characteristics. This highly heterogeneous phylogenetic group of the order Lactobacillales, phylum Firmicutes, comprises primarily Lactobacillus, Leuconostoc, Pediococcus, Lactococcus, and Streptococcus. LAB are typically found in multiple ecosystems on earth, however mainly in decaying plants, dairy products and mucosal cavities. Lactic acid production links them to food fermentation since acidification hinders the growth of food spoilage agents. The industrial and medical importance of LAB is also demonstrated by their „generally recognized as safe” (GRAS) status.
Besides the mediated by lactic acid and H2O2 anti-microbial properties of LAB, specific bacteriocin-based mechanisms can control bacterial growth in distinct environments and provide an additional barrier to spoilage and pathogenic bacteria. Bacteriocins are ribosomally synthesized peptides or proteins with bactericidal or bacteriostatic activities. Their established or future applications of bacteriocins include their use as biopreservative agents, as probiotic-promoting factors, and as antibiotics. All these possible applications drive active research, aiming at identifying new bacteriocins, their mechanism of action and resistance that they develop in bacteria. We identified mannose phosphotransferase system (Man-PTS) as a receptor for a number of non-homologous bacteriocins with greatly different activity spectra. These bacteriocins use distinct bacteriocin – receptor binding patterns when compared to each other and to the Man-PTS-targeting bacteriocins characterized earlier. Among the specific amino acids from distinct regions of Lactococcus spp. Man-PTS IICD engaged in the bacteriocin – receptor interaction, those from the IID extracellular loop (region γ or γ+) seem to be the most important for the interaction with all bacteriocins. The constructed 3D models of Man-PTS IICD indicated transmembrane localization of subunit IIC and monotopic localization of IID suggesting, respectively, entry and docking receptor functions for these subunits. As we expect that bacteriocins binding Man-PTS constitute a much larger family than the four investigated here, our future studies will focus on a search for other bacteriocins targeting the membrane subunits of Man-PTS. Their detailed investigation will allow us to build a full picture of the bacteriocin – Man-PTS interactions and could eventually justify proposing a separate group of bacteriocins besides the currently recognized IIa-IId.
Resistance to peptide antibiotics affecting the cell envelope is mostly associated with the action of peptide-sensing and detoxification (PSD) modules, which consist of a two-component system (TCS) and an ATP-binding cassette (ABC) transporter. On the other hand, the knowledge about the mechanisms of resistance to bacteriocins and possible cross-resistance between them and antibiotics is scarce. We show that Lactococcus lactis acquires resistance to AurA53- and EntL50-like bacteriocins and cross-resistance to membrane-active peptide antibiotics through the accumulation of gain-of-function point mutations in genes encoding components of the YsaCB-KinG-LlrG PSD module. In the case of YsaB permease, the critical driver of resistance to these antimicrobials is the mutation-conditioned dissociation of its N-terminal FtsX domain, while its central and C-terminal parts are dispensable in this process. The function of the FtsX domain is dependent on the presence of the ATPase YsaC and the transcriptional regulator LlrG suggesting a cascade of resistance acquisition from activating mutations in the ABC transporter YsaCB, resulting in upregulation of LlrG and finally LlrG-dependent activation of genes involved in protective cell envelope remodeling. However, a shortcut to
resistance bypassing the YsaCB system is possible through activating point mutations in llrG. Owing to the distinct resistance mechanisms resulting from the two-domain structure of YsaB, acquisition of resistance to AurA53- and EntL50-like bacteriocins and membrane-active peptide antibiotics results in the increased susceptibility to bacitracin, which provides a rationale for designing multicomponent formulations with appropriately selected composition allowing to avoid the risk of resistance development.
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