Aurantimycin resistance genes contribute to survival of Listeria monocytogenes during life in the environment

Abstract

Summary Bacteria can cope with toxic compounds such as antibiotics by inducing genes for their detoxification. A common detoxification strategy is compound excretion by ATP‐binding cassette (ABC) transporters, which are synthesized upon compound contact. We previously identified the multidrug resistance ABC transporter LieAB in Listeria monocytogenes, a Gram‐positive bacterium that occurs ubiquitously in the environment, but also causes severe infections in humans upon ingestion. Expression of the lieAB genes is strongly induced in cells lacking the PadR‐type transcriptional repressor LftR, but compounds leading to relief of this repression in wild‐type cells were not known. Using RNA‐Seq and promoter‐lacZ fusions, we demonstrate highly specific repression of the lieAB and lftRS promoters through LftR. Screening of a natural compound library yielded the depsipeptide aurantimycin A – synthesized by the soil‐dwelling Streptomyces aurantiacus – as the first known naturally occurring inducer of lieAB expression. Genetic and phenotypic experiments concordantly show that aurantimycin A is a substrate of the LieAB transporter and thus, lftRS and lieAB represent the first known genetic module conferring and regulating aurantimycin A resistance. Collectively, these genes may support the survival of L. monocytogenes when it comes into contact with antibiotic‐producing bacteria in the soil.

Mild Stress Conditions during Laboratory Culture Promote the Proliferation of Mutations That Negatively Affect Sigma B Activity in Listeria monocytogenes

“…The data presented here suggest an explanation for the common detection of mutations in the sigB operon of L. monocytogenes (28,(33)(34)(35)(36)55), including an earlier study in our own laboratory where an rsbV missense mutation arose during routine subculture (31).…”

“…The occurrence of sigB operon mutations in this study and in other studies (28,31,(33)(34)(35)(36) prompted us to investigate whether undocumented premature stop codons (PMSCs) might be present in the sigB operon in genome sequences deposited in public databases, so we searched for PMSCs in the sigB operon among 22,340 of L. monocytogenes genome assemblies. The PMSC rate per 100 bp (expressed as a % rate per 100 bp to normalise for gene length) for genes in the sigB operon that positively affect σ B activity (rsbV, rsbT and rsbU) was considerably higher than for genes that act negatively (rsbW and rsbX).…”

“…The emergence of mutations in the sigB operon of L. monocytogenes during laboratory culture has been reported in a number of other studies (28,31,(33)(34)(35). It has been suggested that the occurrence of mutations impairing σ B function might be particularly associated with loss of surface proteins (36).…”

PadR-type repressors controlling production of a non-canonical FtsW/RodA homologue and other trans-membrane proteins

“…Recently, we demonstrated that this efflux pump is expressed when L . monocytogenes comes into contact with aurantimycin A 21 , a depsipeptide antibiotic with very potent bactericidal activity against Gram-positive bacteria and produced by soil-dwelling Streptomyces aurantiacus 22 . Thus, LftR and LieAB likely promote survival of L .…”

“…monocytogenes when it comes in contact with S . aurantiacus in the soil, its natural reservoir 21 , from where it may eventually enter the food chain.…”