TheBacillus subtiliscell envelope stress-inducibleytpABoperon modulates membrane properties and contributes to bacitracin resistance

Author:

Willdigg Jessica R.,Patel Yesha,Arquilevich Briana E.,Subramanian Chitra,Frank Matthew W.,Rock Charles O.,Helmann John D.ORCID

Abstract

AbstractAntibiotics that inhibit peptidoglycan synthesis trigger the activation of both specific and general protective responses. σMresponds to diverse antibiotics that inhibit cell wall synthesis. Here, we demonstrate that cell wall inhibiting drugs, such as bacitracin and cefuroxime, induce the σM-dependentytpABoperon. YtpA is a predicted hydrolase previously proposed to generate the putative lysophospholipid antibiotic bacilysocin (lysophosphatidylglycerol), and YtpB is the branchpoint enzyme for the synthesis of membrane-localized C35terpenoids. Using targeted lipidomics we reveal that YtpA is not required for the production of lysophosphatidylglycerol. Nevertheless,ytpAwas critical for growth in a mutant strain defective for homeoviscous adaptation due to a lack of genes for the synthesis of branched chain fatty acids and the Des phospholipid desaturase. Consistently, overexpression ofytpAincreased membrane fluidity as monitored by fluorescence anisotropy. TheytpAgene contributes to bacitracin resistance in mutants additionally lacking thebceABorbcrCgenes, which directly mediate bacitracin resistance. These epistatic interactions support a model in which σM-dependent induction of theytpABoperon helps cells tolerate bacitracin stress, either by facilitating the flipping of the undecaprenyl-phosphate carrier lipid or by impacting the assembly or function of membrane-associated complexes proteins involved in cell wall homeostasis.ImportancePeptidoglycan synthesis inhibitors include some of our most important antibiotics. InBacillus subtilis, peptidoglycan synthesis inhibitors induce the σMregulon, which is critical for intrinsic antibiotic resistance. The σM-dependentytpABoperon encodes a predicted hydrolase (YtpA) and the enzyme that initiates the synthesis of C35terpenoids (YtpB). Our results suggest that YtpA is critical in cells defective in homeoviscous adaptation. Further, we find that YtpA functions cooperatively with the BceAB and BcrC proteins in conferring intrinsic resistance to bacitracin, a peptide antibiotic that binds tightly to the UPP lipid carrier that sustains peptidoglycan synthesis.

Publisher

Cold Spring Harbor Laboratory

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