In this section
@article{Nolan:2022:10.1101/2022.09.01.506298,
author = {Nolan, AC and Zeden, MS and Campbell, C and Kviatkovski, I and Urwin, L and Corrigan, RM and Gründling, A and OGara, JP},
doi = {10.1101/2022.09.01.506298},
title = {Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitise MRSA to β-lactam antibiotics},
url = {http://dx.doi.org/10.1101/2022.09.01.506298},
year = {2022}
}
TY - JOUR
AB - <jats:title>Abstract</jats:title><jats:p>Elucidating the complex mechanisms controlling <jats:italic>mecA</jats:italic>/PBP2a-mediated β-lactam resistance in methicillin resistant <jats:italic>Staphylococcus aureus</jats:italic> (MRSA) has the potential to identify new drug targets with therapeutic potential. Here, we report that mutations that interfere with <jats:italic>de novo</jats:italic> purine synthesis (<jats:italic>pur</jats:italic> operon), purine transport (NupG, PbuG and PbuX) and the nucleotide salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Extrapolating from these findings, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis were shown to significantly reduce MRSA β-lactam resistance. In contrast adenosine, which is fluxed to ATP, significantly increased oxacillin resistance, whereas inosine, which can be fluxed to ATP and GTP via hypoxanthine, only marginally reduced the oxacillin MIC. Increased oxacillin resistance of the <jats:italic>nupG</jats:italic> mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which in turn is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including <jats:italic>nupG</jats:italic> and <jats:italic>hpt</jats:italic>. Microscopic analysis revealed that guanosine significantly increased cell size, a phenotype also associated with reduced levels of c-di-AMP. Consistent with this, guanosine significantly reduced levels of c-di-AMP, and inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in <jats:italic>nupG</jats:italic> or <jats:italic>deoD2</jats:
AU - Nolan,AC
AU - Zeden,MS
AU - Campbell,C
AU - Kviatkovski,I
AU - Urwin,L
AU - Corrigan,RM
AU - Gründling,A
AU - OGara,JP
DO - 10.1101/2022.09.01.506298
PY - 2022///
TI - Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitise MRSA to β-lactam antibiotics
UR - http://dx.doi.org/10.1101/2022.09.01.506298
UR - https://doi.org/10.1101/2022.09.01.506298
ER -
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