TY - JOUR
T1 - Malleilactone is a Burkholderia pseudomallei virulence factor regulated by antibiotics and quorum sensing
AU - Klaus, Jennifer R.
AU - Deay, Jacqueline
AU - Neuenswander, Benjamin
AU - Hursh, Wyatt
AU - Gao, Zhe
AU - Bouddhara, Tiffany
AU - Williams, Todd D.
AU - Douglas, Justin
AU - Monize, Kyle
AU - Martins, Patricia
AU - Majerczyk, Charlotte
AU - Seyedsayamdost, Mohammad R.
AU - Peterson, Blake R.
AU - Rivera, Mario
AU - Chandler, Josephine R.
N1 - Funding Information:
We thank Amy Schaefer, P. Scott Hefty, Lynn Hancock, and Brian Ackley for helpful discussions. This work was supported by startup funds from the University of Kansas to J.R.C. and by a NIH COBRE Center for Molecular Analysis of Disease Pathways Research Project Award to J.R.C. and B.R.P. (grant P20GM103638). B.N. was supported by the NIH KU Legacy Chemical Methodologies and Library Development program (grant R24GM111385) and by the COBRE CMADP Chemical Biology Core (grant P20GM103638). B.R.P. thanks the NIH (grant R01 CA211720) for financial support. Support for the NMR instrumentation was provided by NIH Shared Instrumentation Grant (grant S10RR024664) and by a NSF Major Research Instrumentation Award (grant 1625923). M.R. thanks NIH (RO1 AI125529) and NSF (MCB-1615767) for financial support
Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Burkholderia pseudomallei, the causative agent of melioidosis, encodes almost a dozen predicted polyketide (PK) biosynthetic gene clusters. Many of these are regulated by LuxR-I-type acyl-homoserine (AHL) quorum-sensing systems. One of the PK gene clusters, the mal gene cluster, is conserved in the close relative Burkholderia thailandensis. The B. thailandensis mal genes code for the cytotoxin malleilactone and are regulated by a genetically linked LuxR-type transcription factor, MalR. Although AHLs typically interact with LuxR-type proteins to modulate gene transcription, the B. thailandensis MalR does not appear to be an AHL receptor. Here, we characterize the mal genes and MalR in B. pseudomallei. We use chemical analyses to demonstrate that the B. pseudomallei mal genes code for malleilactone. Our results show that MalR and the mal genes contribute to the ability of B. pseudomallei to kill Caenorhabditis elegans. In B. thailandensis, antibiotics like trimethoprim can activate MalR by driving transcription of the mal genes, and we demonstrate that some of the same antibiotics induce expression of B. pseudomallei malR. We also demonstrate that B. pseudomallei MalR does not respond directly to AHLs. Our results suggest that MalR is indirectly repressed by AHLs, possibly through a repressor, ScmR. We further show that malleilactone is a B. pseudomallei virulence factor and provide the foundation for understanding how malleilactone contributes to the pathology of melioidosis infections.
AB - Burkholderia pseudomallei, the causative agent of melioidosis, encodes almost a dozen predicted polyketide (PK) biosynthetic gene clusters. Many of these are regulated by LuxR-I-type acyl-homoserine (AHL) quorum-sensing systems. One of the PK gene clusters, the mal gene cluster, is conserved in the close relative Burkholderia thailandensis. The B. thailandensis mal genes code for the cytotoxin malleilactone and are regulated by a genetically linked LuxR-type transcription factor, MalR. Although AHLs typically interact with LuxR-type proteins to modulate gene transcription, the B. thailandensis MalR does not appear to be an AHL receptor. Here, we characterize the mal genes and MalR in B. pseudomallei. We use chemical analyses to demonstrate that the B. pseudomallei mal genes code for malleilactone. Our results show that MalR and the mal genes contribute to the ability of B. pseudomallei to kill Caenorhabditis elegans. In B. thailandensis, antibiotics like trimethoprim can activate MalR by driving transcription of the mal genes, and we demonstrate that some of the same antibiotics induce expression of B. pseudomallei malR. We also demonstrate that B. pseudomallei MalR does not respond directly to AHLs. Our results suggest that MalR is indirectly repressed by AHLs, possibly through a repressor, ScmR. We further show that malleilactone is a B. pseudomallei virulence factor and provide the foundation for understanding how malleilactone contributes to the pathology of melioidosis infections.
KW - Burkholderia
KW - Polyketide
KW - Quorum sensing
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U2 - 10.1128/JB.00008-18
DO - 10.1128/JB.00008-18
M3 - Article
C2 - 29735757
AN - SCOPUS:85049195920
SN - 0021-9193
VL - 200
JO - Journal of Bacteriology
JF - Journal of Bacteriology
IS - 14
M1 - e00008-18
ER -