The menaquinone pathway is important for susceptibility of Staphylococcus aureus to the antibiotic adjuvant, cannabidiol
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The menaquinone pathway is important for susceptibility of Staphylococcus aureus to the antibiotic adjuvant, cannabidiol. / Wassmann, Claes Søndergaard; Rolsted, Andreas Pryds; Lyngsie, Mie Cecilie; Torres-Puig, Sergi; Kronborg, Tina; Vestergaard, Martin; Ingmer, Hanne; Pontoppidan, Steen Plesner; Klitgaard, Janne Kudsk.
I: Microbiological Research, Bind 257, 126974, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - The menaquinone pathway is important for susceptibility of Staphylococcus aureus to the antibiotic adjuvant, cannabidiol
AU - Wassmann, Claes Søndergaard
AU - Rolsted, Andreas Pryds
AU - Lyngsie, Mie Cecilie
AU - Torres-Puig, Sergi
AU - Kronborg, Tina
AU - Vestergaard, Martin
AU - Ingmer, Hanne
AU - Pontoppidan, Steen Plesner
AU - Klitgaard, Janne Kudsk
N1 - Publisher Copyright: © 2022 The Authors
PY - 2022
Y1 - 2022
N2 - Emergence of antibiotic resistant bacteria is evolving at an alarming pace; therefore, we must start turning to alternative approaches. One of these, could be the use of antibiotic adjuvants that enhances the effect of antibiotics towards resistant bacteria. A novel antibiotic adjuvant is cannabidiol (CBD), which we have previously shown can enhance the effect of bacitracin (BAC). BAC targets cell wall synthesis by inhibiting dephosphorylation of the lipid carrier undecaprenyl pyrophosphate prior to recycling across the membrane. However, the mechanism underlying this CBD mediated potentiation of BAC has remained unknown. To explore this, we examined resistance to CBD in Staphylococcus aureus through daily exposures to CBD. By subsequent whole genome sequencing, we observed multiple genes to be mutated, including the farE/farR system encoding a fatty acid efflux pump (FarE) and its regulator (FarR). Importantly, recreation of mutations in these genes showed decreased susceptibility towards the combination of CBD and BAC. Furthermore, we searched the Nebraska Transposon Mutant Library for CBD susceptible strains and identified menH encoding a protein participating in menaquinone biosynthesis. Strains containing deletions in this and other menaquinone related genes showed increased susceptibility towards CBD, while addition of exogenous menaquinone reversed the effect and reduced susceptible towards CBD. These results suggest that CBD potentiates BAC by redirecting the isoprenoid precursor isopentenyl pyrophosphate towards production of menaquinone rather than the lipid carrier undecaprenyl pyrophosphate, which dephosphorylation is inhibited by BAC. This in turn might decrease the level of undecaprenyl pyrophosphate thus enhancing the effect of BAC. Our study illustrates how antibiotic adjuvants may apply to enhance efficacy of antimicrobial compounds.
AB - Emergence of antibiotic resistant bacteria is evolving at an alarming pace; therefore, we must start turning to alternative approaches. One of these, could be the use of antibiotic adjuvants that enhances the effect of antibiotics towards resistant bacteria. A novel antibiotic adjuvant is cannabidiol (CBD), which we have previously shown can enhance the effect of bacitracin (BAC). BAC targets cell wall synthesis by inhibiting dephosphorylation of the lipid carrier undecaprenyl pyrophosphate prior to recycling across the membrane. However, the mechanism underlying this CBD mediated potentiation of BAC has remained unknown. To explore this, we examined resistance to CBD in Staphylococcus aureus through daily exposures to CBD. By subsequent whole genome sequencing, we observed multiple genes to be mutated, including the farE/farR system encoding a fatty acid efflux pump (FarE) and its regulator (FarR). Importantly, recreation of mutations in these genes showed decreased susceptibility towards the combination of CBD and BAC. Furthermore, we searched the Nebraska Transposon Mutant Library for CBD susceptible strains and identified menH encoding a protein participating in menaquinone biosynthesis. Strains containing deletions in this and other menaquinone related genes showed increased susceptibility towards CBD, while addition of exogenous menaquinone reversed the effect and reduced susceptible towards CBD. These results suggest that CBD potentiates BAC by redirecting the isoprenoid precursor isopentenyl pyrophosphate towards production of menaquinone rather than the lipid carrier undecaprenyl pyrophosphate, which dephosphorylation is inhibited by BAC. This in turn might decrease the level of undecaprenyl pyrophosphate thus enhancing the effect of BAC. Our study illustrates how antibiotic adjuvants may apply to enhance efficacy of antimicrobial compounds.
KW - Antibiotic
KW - Bacitracin
KW - Cannabidiol
KW - Menaquinone
KW - Resistance
U2 - 10.1016/j.micres.2022.126974
DO - 10.1016/j.micres.2022.126974
M3 - Journal article
C2 - 35091344
AN - SCOPUS:85123740060
VL - 257
JO - Microbiological Research
JF - Microbiological Research
SN - 0944-5013
M1 - 126974
ER -
ID: 291604877