Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

Abstract

NAI-112, a glycosylated, labionine-containing lanthipeptide with weak antibacterial activity, has demonstrated analgesic activity in relevant mouse models of nociceptive and neuropathic pain. However, the mechanism(s) through which NAI-112 exerts its analgesic and antibacterial activities is not known. In this study, we analyzed changes in the spinal cord lipidome resulting from treatment with NAI-112 of naive and in-pain mice. Notably, NAI-112 led to an increase in phosphatidic acid levels in both no-pain and pain models and to a decrease in lysophosphatidic acid levels in the pain model only. We also showed that NAI-112 can form complexes with dipalmitoyl-phosphatidic acid and that Staphylococcus aureus can become resistant to NAI-112 through serial passages at sub-inhibitory concentrations of the compound. The resulting resistant mutants were phenotypically and genotypically related to vancomycin-insensitive S. aureus strains, suggesting that NAI-112 binds to the peptidoglycan intermediate lipid II. Altogether, our results suggest that NAI-112 binds to phosphate-containing lipids and blocks pain sensation by decreasing levels of lysophosphatidic acid in the TRPV1 pathway.

Allopeptimicins: unique antibacterial metabolites generated by hybrid PKS-NRPS, with original self-defense mechanism in Actinoallomurus

“…S16B † ). Consistently, when tested against different S. aureus mutants selected through serial passages, phenotypically and genotypically related to vancomycin insensitive S. aureus (VISA) strains, 36 we observed an increase in the MIC of allopeptimicins A (Fig. S16c † ).…”

“…Against these same mutants, a similar shi in MICs was observed for other bona de antibiotics that bind to the essential peptidoglycan precursor lipid II such as vancomycin, ramoplanin and NAI-107. 36 Self-defense mechanism in the producer strain Actinoallomurus sp. ID145808…”

Mechanism of Action of Ribosomally Synthesized and Post-Translationally Modified Peptides

“…(Figure ) also showed efficacy in the treatment of neuropathic pain . In mouse model studies, both compounds displayed a decrease in allodynia while NAI-112 also reduced hyperalgesia. , While neither LabyA2 nor NAI-112 have a known MOA for these activities, it has been proposed that NAI-112 may interact with the vanilloid pathway and that the molecule blocks pain sensation by decreasing the levels of lysophosphatidic acid (LPA) and increasing the levels of phosphatidic acid . LPA activates the vanilloid receptor 1 (also known as capsaicin receptor and TRPV1), triggering pain.…”

“…LPA activates the vanilloid receptor 1 (also known as capsaicin receptor and TRPV1), triggering pain. NAI-112 also exhibits modest antibiotic activity with micromolar MIC values against various staphylococci and streptococci. , NAI-112 was initially identified as a cell wall inhibitor, with resistance mutants suggesting that the peptidoglycan intermediate lipid II (Figure ) may be a target …”

Allopeptimicins: unique antibacterial metabolites generated by hybrid PKS-NRPS, with original self-defense mechanism in Actinoallomurus

“…Fig. S16.A) time-kill profiles of allopeptimicin A against S. aureus ATCC6538P; B) Impact of allopeptimicins A on macromolecules synthesis by S. aureus cells: DNA (blue diamonds), RNA (orange squares), protein (grey triangles), and cell wall (yellow circles); C) growth curve of S. aureus ATCC6538P (dashed lines) and mutant R15.536 (solid lines) in the presence of allopeptimicin A.…”