Lactococcus lactis resistance to aureocin A53- and enterocin L50-like bacteriocins and membrane-targeting peptide antibiotics relies on the YsaCB-KinG-LlrG four-component system

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Abstract

Resistance to non-ribosomally synthesized peptide antibiotics affecting the cell envelope is well-studied and 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. In contrast, the resistance mechanisms to ribosomally synthesized bacterial toxic peptides (bacteriocins), which also affect the cell envelope, are studied to lesser extent, and possible cross-resistance between them and antibiotics is still poorly understood. In the present study, we investigated the development of resistance of Lactococcus lactis to aureocin A53- and enterocin L50-like bacteriocins and cross-resistance with antibiotics. First, 19 spontaneous mutants resistant to their representatives were selected and displayed changes in the sensitivity also to peptide antibiotics acting on the cell envelope (bacitracin, daptomycin, and gramicidin). Sequencing of their genomes revealed mutations in genes encoding ABC transporter YsaCB and TCS KinG-LlrG, the emergence of which induced upregulation of the dltABCD and ysaDCB operons. The ysaB mutations were either nonsense or frameshift and led to the generation of truncated YsaB but with the conserved N-terminal FtsX domain intact. Deletions of ysaCB or llrG had a minor effect on the resistance of the obtained mutants to the tested bacteriocins, daptomycin, and gramicidin, indicating that the development of resistance is dependent on the modification of the protein rather than its absence. In further corroboration of the above conclusion, we show that the FtsX domain, which functions effectively when the YsaB is lacking its central and C-terminal parts, is critical for the resistance to these antimicrobials.

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• Lactococcus lactis resistance to aureocin A53- and enterocin L50-like bacteriocins and membrane-targeting peptide antibiotics relies on the YsaCB-KinG-LlrG four-component system. (deposited UNSPECIFIED)
  • Lactococcus lactis resistance to aureocin A53- and enterocin L50-like bacteriocins and membrane-targeting peptide antibiotics relies on the YsaCB-KinG-LlrG four-component system. (deposited 13 Jul 2023 07:08) [Currently Displayed]