Impact of a Cross-Kingdom Signaling Molecule of Candida albicans on Acinetobacter baumannii Physiology.
Multidrug-resistant (MDR) Acinetobacter baumannii is an opportunistic human pathogen that has become highly problematic in the clinical environment. Novel therapies are desperately required. To assist in identifying new therapeutic targets, the antagonistic interactions between A. baumannii and the most common human fungal pathogen, Candida albicans, were studied. We have observed that the C. albicans quorum-sensing molecule, farnesol, has cross-kingdom interactions, affecting the viability of A. baumannii. To gain an understanding of its mechanism, the transcriptional profile of A. baumannii exposed to farnesol was examined. Farnesol caused dysregulation of a large number of genes involved in cell membrane biogenesis, multidrug efflux pumps (AcrAB-like and AdeIJK-like), and A. baumannii virulence traits such as biofilm formation (csuA, csuB, and ompA) and motility (pilZ and pilH). We also observed a strong induction in genes involved in cell division (minD, minE, ftsK, ftsB, and ftsL). These transcriptional data were supported by functional assays showing that farnesol disrupts A. baumannii cell membrane integrity, alters cell morphology, and impairs virulence characteristics such as biofilm formation and twitching motility. Moreover, we showed that A. baumannii uses efflux pumps as a defense mechanism against this eukaryotic signaling molecule. Owing to its effects on membrane integrity, farnesol was tested to see if it potentiated the activity of the membrane-acting polymyxin antibiotic colistin. When coadministered, farnesol increased sensitivity to colistin for otherwise resistant strains. These data provide mechanistic understanding of the antagonistic interactions between diverse pathogens and may provide important insights into novel therapeutic strategies.
Department of Microbiology, Monash University, Melbourne, Australia.
Xenia
X
Kostoulias
Department of Microbiology, Monash University, Melbourne, Australia.
Gerald L
GL
Murray
Department of Microbiology, Monash University, Melbourne, Australia.
Gustavo M
GM
Cerqueira
Department of Microbiology, Monash University, Melbourne, Australia.
Jason B
JB
Kong
Department of Microbiology, Monash University, Melbourne, Australia.
Farkad
F
Bantun
Infectious Diseases Division, Brown University and Rhode Island Hospital, Providence, Rhode Island, USA.
Eleftherios
E
Mylonakis
Department of Microbiology, Monash University, Melbourne, Australia.
Chen Ai
CA
Khoo
Department of Microbiology, Monash University, Melbourne, Australia Department of Infectious Diseases, Central Clinical School, Alfred Hospital and Monash University, Melbourne, Australia anton.peleg@monash.edu.
Anton Y
AY
Peleg
D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000898:Antibiosis; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000472:pathogenicity* / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects; D003091:Colistin / Q000494:pharmacology; D004357:Drug Synergism; D005204:Farnesol / Q000378:metabolism / Q000494:pharmacology*; D015964:Gene Expression Regulation, Bacterial; D019450:Genes, MDR; D053038:Quorum Sensing; D059467:Transcriptome / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005204:Farnesol; D003091:Colistin