Abstract：
:Peptidoglycan synthesis is an important target for antibiotics and relies on intermediates derived from central metabolism. As a result, alterations of metabolism may affect antibiotic sensitivity. An aspB mutant is auxotrophic for aspartate (Asp) and asparagine (Asn) and lyses when grown in Difco sporulation medium (DSM), but not in LB medium. Genetic and physiological studies, supported by amino acid analysis, reveal that cell lysis in DSM results from Asp limitation due to a relatively low Asp and high glutamate (Glu) concentrations, with Glu functioning as a competitive inhibitor of Asp uptake by the major Glu/Asp transporter GltT. Lysis can be specifically suppressed by supplementation with 2,6-diaminopimelate (DAP), which is imported by two different cystine uptake systems. These studies suggest that aspartate limitation depletes the peptidoglycan precursor meso-2,6-diaminopimelate (mDAP), inhibits peptidoglycan synthesis, upregulates the cell envelope stress response mediated by σM and eventually leads to cell lysis. Aspartate limitation sensitizes cells to antibiotics targeting late steps of PG synthesis, but not steps prior to the addition of mDAP into the pentapeptide sidechain. This work highlights the ability of perturbations of central metabolism to sensitize cells to peptidoglycan synthesis inhibitors.
journal_name
Mol Microbioljournal_title
Molecular microbiologyauthors
Zhao H,Roistacher DM,Helmann JDdoi
10.1111/mmi.14078subject
Has Abstractpub_date
2018-09-01 00:00:00pages
826-844issue
6eissn
0950-382Xissn
1365-2958journal_volume
109pub_type
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