scholarly journals MgrB dependent colistin resistance in Klebsiella pneumoniae is associated with an increase in host-to-host transmission

2021 ◽  
Author(s):  
Andrew S. Bray ◽  
Richard D. Smith ◽  
Andrew W. Hudson ◽  
Giovanna E. Hernandez ◽  
Taylor M. Young ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Murine Model ◽  
Regulatory Protein ◽  
Common Mutation ◽  
Colistin Resistance ◽  
Two Component System ◽  
Component System ◽  
Gut Colonization ◽  
Two Component ◽  
Biological Cost

AbstractDue to its high transmissibility, Klebsiella pneumoniae (Kpn) is one of the leading causes of nosocomial infections. Here, we studied the biological cost of colistin resistance, an antibiotic of last resort, of this opportunistic pathogen using a murine model of gut colonization and transmission. Colistin resistance in Kpn is commonly the result of inactivation of the small regulatory protein MgrB. Without a functional MgrB, the two-component system PhoPQ is constitutively active, leading to increased lipid A modifications and subsequent colistin resistance. Using an engineered MgrB mutant, we observed that MgrB-dependent colistin resistance is not associated with a fitness defect during in vitro growth conditions. However, colistin-resistant Kpn colonizes the murine gut poorly, which may be due to the decreased production of capsular polysaccharide by the mutant. The colistin-resistant mutant of Kpn had increased survival outside the host when compared to the parental colistin-sensitive strain. We attribute this enhanced survivability to dysregulation of the PhoPQ two-component system and accumulation of the master stress regulator RpoS. The enhanced survival of the colistin resistant strain may be a key factor in the observed rapid host-to-host transmission in our model. Together, our data demonstrate that colistin-resistant Kpn experiences a biological cost in gastrointestinal colonization. However, this cost is mitigated by enhanced survival outside the host, increasing the risk of transmission. Additionally, it underscores the importance of considering the entire life cycle of a pathogen to truly determine the biological cost associated with antibiotic resistance.ImportanceThe biological cost associated with colistin resistance in Klebsiella pneumoniae (Kpn) was examined using a murine model of Kpn gut colonization and fecal-oral transmission. A common mutation resulting in colistin resistance in Kpn is a loss-of-function mutation of the small regulatory protein MgrB that regulates the two-component system PhoPQ. Even though colistin resistance in Kpn comes with a fitness defect in gut colonization, it increases bacterial survival outside the host enabling it to more effectively transmit to a new host. The enhanced survival is dependent upon the accumulation of RpoS and dysregulation of the PhoPQ. Hence, our study expands our understanding of the underlying molecular mechanism contributing to the transmission of colistin-resistant Kpn.

scholarly journals Identification of a Second Two-Component Signal Transduction System That Controls Fosfomycin Tolerance and Glycerol-3-Phosphate Uptake

2014 ◽  
Vol 197 (5) ◽  
pp. 861-871 ◽  
Author(s):  
Kumiko Kurabayashi ◽  
Yuko Hirakawa ◽  
Koichi Tanimoto ◽  
Haruyoshi Tomita ◽  
Hidetada Hirakawa
Keyword(s):  
Phosphate Uptake ◽  
Response Regulator ◽  
Anaerobic Respiration ◽  
Regulatory System ◽  
Carbon Substrate ◽  
Two Component System ◽  
Component System ◽  
Content Type ◽  
Two Component ◽  
Biological Cost

Particular interest in fosfomycin has resurfaced because it is a highly beneficial antibiotic for the treatment of refractory infectious diseases caused by pathogens that are resistant to other commonly used antibiotics. The biological cost to cells of resistance to fosfomycin because of chromosomal mutation is high. We previously found that a bacterial two-component system, CpxAR, induces fosfomycin tolerance in enterohemorrhagicEscherichia coli(EHEC) O157:H7. This mechanism does not rely on irreversible genetic modification and allows EHEC to relieve the fitness burden that results from fosfomycin resistance in the absence of fosfomycin. Here we show that another two-component system, TorSRT, which was originally characterized as a regulatory system for anaerobic respiration utilizing trimethylamine-N-oxide (TMAO), also induces fosfomycin tolerance. Activation of the Tor regulatory pathway by overexpression oftorR, which encodes the response regulator, or addition of TMAO increased fosfomycin tolerance in EHEC. We also show that phosphorylated TorR directly represses the expression ofglpT, a gene that encodes a symporter of fosfomycin and glycerol-3-phosphate, and activation of the TorR protein results in the reduced uptake of fosfomycin by cells. However, cells in which the Tor pathway was activated had an impaired growth phenotype when cultured with glycerol-3-phosphate as a carbon substrate. These observations suggest that the TorSRT pathway is the second two-component system to reversibly control fosfomycin tolerance and glycerol-3-phosphate uptake in EHEC, and this may be beneficial for bacteria by alleviating the biological cost. We expect that this mechanism could be a potential target to enhance the utility of fosfomycin as chemotherapy against multidrug-resistant pathogens.

scholarly journals Paucity of adaptive selection in PmrAB two-component system may resist emergence of colistin resistance in Acinetobacter baumannii

2019 ◽  
Author(s):  
Sudhakar Pagal ◽  
Rajagopalan Saranathan ◽  
Anshu Rani ◽  
Archana Tomar ◽  
K. P. Arunkumar ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Selection Pressure ◽  
Minor Role ◽  
Colistin Resistance ◽  
Two Component System ◽  
Adaptive Selection ◽  
Component System ◽  
Adaptive Mutations ◽  
Selection Analysis ◽  
Two Component

AbstractInvestigations on the selection pressure acting on point mutations in PmrAB two-component system may provide insights into the future of colistin therapy in Acinetobacter baumannii, since mutations in pmrAB are implicated in colistin resistance. We performed adaptive selection analysis of pmrAB and compared with the available data on colistin resistant strains. We analysed PmrAB sequences in 3113 draft genomes of A. baumannii obtained from RefSeq database. Adaptive selection analysis was performed by two widely used programs namely, HyPhy and PAML. In addition, to examine the reliability of the approach, the same analysis was performed on gyrA of Escherichia coli and Salmonella enterica, since adaptive mutations on gyrA confer quinolone resistance. Mutations that had caused colistin resistance were found to be neither adaptive nor polymorphic, rather they occur at sites that are either under neutral or purifying selection. Strong negative evolutionary selection pressure is also observed at sites throughout both PmrA and PmrB. Sites with high levels of polymorphisms in PmrAB were found to be under neutral selection. Notably, there was no sign of positive selection. Some of them are rather deleterious. These conditions might be maintaining the incidence of colistin resistance in A. baumannii under check. Therefore, in the context of colistin resistance, natural selection plays only a minor role and we assert that in future, A. baumannii may not be able to sustain and successfully disseminate colistin resistance. Therefore, at present the concerns raised about continuing the usage of colistin for the treatment against A. baumannii infections appears to be unnecessary.

scholarly journals Various novel colistin resistance mechanisms interact to facilitate adaptation of Aeromonas hydrophila to complex colistin environments

2021 ◽  
Author(s):  
Junqi Liu ◽  
Gang Xiao ◽  
Wangping Zhou ◽  
Jun Yang ◽  
Yang Wang ◽  
...  
Keyword(s):  
Aeromonas Hydrophila ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Bacterial Survival ◽  
Colistin Resistance ◽  
Two Component System ◽  
Component System ◽  
Gram Negative ◽  
Two Component ◽  
High Level

Aeromonas hydrophila, a heterotrophic and Gram-negative bacterium, has attracted considerable attention owing to the increasing prevalence of reported infections. Colistin is a last-resort antibiotic that can treat life-threatening infections caused by multidrug-resistant gram-negative bacteria. However, the mechanisms underlying colistin resistance in A. hydrophila remain unclear. The present study reveals four novel colistin resistance mechanisms in A. hydrophila: (i) EnvZ/OmpR upregulates the expression of the arnBCADTEF operon to mediate LPS modification by 4-amino-4-deoxy-L-arabinose; (ii) EnvZ/OmpR regulates the expression of the autotransporter gene3832 to decrease outer membrane permeability in response to colistin; (iii) deletion of envZ/ompR activates PhoP/PhoQ, which functions as a substitute two-component system to mediate the addition of phosphoethanolamine to lipid A via pmrC; and (iv) the mlaFD173A mutant confers high-level colistin resistance via upregulation of the Mla pathway. The EnvZ/OmpR two-component system-mediated resistance mechanism is the leading form of colistin resistance in A. hydrophila, which enables it to rapidly generate low- to medium-level colistin resistance. As colistin concentrations in the environment continue to rise, antibiotic resistance mediated by EnvZ/OmpR becomes insufficient to ensure bacterial survival. Consequently, A. hydrophila has developed a mlaF mutation that results in high-level colistin resistance. Our findings indicate that A. hydrophila can thrive in a complex environment through various colistin resistance mechanisms.

scholarly journals Salmonella entericaSerovar Typhimurium CpxRA Two-Component System Contributes to Gut Colonization inSalmonella-Induced Colitis

2018 ◽  
Vol 86 (7) ◽  
pp. e00280-18 ◽  
Author(s):  
Mayuka Fujimoto ◽  
Ryosuke Goto ◽  
Takeshi Haneda ◽  
Nobuhiko Okada ◽  
Tsuyoshi Miki
Keyword(s):  
Stress Response ◽  
Growth Media ◽  
Two Component System ◽  
Bacterial Gene ◽  
Component System ◽  
Content Type ◽  
Bacterial Gene Expression ◽  
Gut Colonization ◽  
Envelope Stress ◽  
Two Component

ABSTRACTSalmonella enterica, a common cause of diarrhea, has to colonize the gut lumen to elicit disease. In the gut, the pathogen encounters a vast array of environmental stresses that cause perturbations in the bacterial envelope. The CpxRA two-component system monitors envelope perturbations and responds by altering the bacterial gene expression profile. This allowsSalmonellato survive under such harmful conditions. Therefore, CpxRA activation is likely to contribute toSalmonellagut infection. However, the role of the CpxRA-mediated envelope stress response inSalmonella-induced diarrhea is unclear. Here, we show that CpxRA is dispensable for the induction of colitis byS. entericaserovar Typhimurium, whereas it is required for gut colonization. We prove that CpxRA is expressed during gut infection and that the presence of antimicrobial peptides in growth media activates the expression of CpxRA-regulated genes. In addition, we demonstrate that aS. Typhimurium strain lacking thecpxRAgene is able to cause colitis but is unable to continuously colonize the gut. Finally, we show that CpxRA-dependent gut colonization requires the host gut inflammatory response, while DegP, a CpxRA-regulated protease, is dispensable. Our findings reveal that the CpxRA-mediated envelope stress response plays a crucial role inSalmonellagut infection, suggesting that CpxRA might be a promising therapeutic target for infectious diarrhea.

scholarly journals Functional Characterization of a Novel Outer Membrane Porin KpnO, Regulated by PhoBR Two-Component System in Klebsiella pneumoniae NTUH-K2044

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e41505 ◽  
Author(s):  
Vijaya Bharathi Srinivasan ◽  
Manjunath Venkataramaiah ◽  
Amitabha Mondal ◽  
Vasanth Vaidyanathan ◽  
Tanvi Govil ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Outer Membrane ◽  
Functional Characterization ◽  
Two Component System ◽  
Component System ◽  
Outer Membrane Porin ◽  
Two Component

ISAba1-dependent overexpression of eptA in clinical strains of Acinetobacter baumannii resistant to colistin

2019 ◽  
Vol 74 (9) ◽  
pp. 2544-2550 ◽  
Author(s):  
Anaïs Potron ◽  
Jean-Baptiste Vuillemenot ◽  
Hélène Puja ◽  
Pauline Triponney ◽  
Maxime Bour ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Start Codon ◽  
Whole Genome ◽  
Colistin Resistance ◽  
Two Component System ◽  
Component System ◽  
Two Component ◽  
Insertion Sites ◽  
Mutational Activation ◽  
Subsequent Addition

Abstract Background Colistin resistance in Acinetobacter baumannii often results from mutational activation of the two-component system PmrAB and subsequent addition of phospho-ethanolamine (pEtN) to lipooligosaccharide by up-regulated pEtN transferase PmrC. Objectives To characterize mechanisms of colistin resistance independent of PmrCAB in A. baumannii. Methods Twenty-seven colistin-resistant A. baumannii were collected from 2012 to 2018. Analysis of operon pmrCAB was performed by PCR and sequencing. Seven strains were investigated further by WGS and whole-genome MLST (wgMLST). Results Seven out of the 27 selected isolates were found to overexpress eptA, a gene homologous to pmrC, likely as a consequence of upstream insertion of an ISAba1 element. Insertion sites of ISAba1 were mapped 13, 18 and 156 bp ahead of the start codon of eptA in five strains, one strain and one strain, respectively. The finding that the isolates did not cluster together when compared by wgMLST analysis supports the notion that distinct insertion events occurred in close, but different, genetic backgrounds. Conclusions Activation of eptA and subsequent addition of pEtN to the cell surface represents a novel mechanism of resistance to colistin in A. baumannii.

scholarly journals Identification of a Gene Cluster in Klebsiella pneumoniae Which Includes citX, a Gene Required for Biosynthesis of the Citrate Lyase Prosthetic Group

2002 ◽  
Vol 184 (9) ◽  
pp. 2439-2446 ◽  
Author(s):  
Karin Schneider ◽  
Christopher N. Kästner ◽  
Margareta Meyer ◽  
Mirja Wessel ◽  
Peter Dimroth ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Gene Cluster ◽  
Anaerobic Growth ◽  
Insertion Mutant ◽  
Two Component System ◽  
Prosthetic Group ◽  
Component System ◽  
Citrate Lyase ◽  
Two Component ◽  
Citrate Fermentation

ABSTRACT The biosynthesis of the 2′-(5"-phosphoribosyl)-3′-dephospho-coenzyme A (CoA) prosthetic group of citrate lyase (EC 4.1.3.6), a key enzyme of citrate fermentation, proceeds via the initial formation of the precursor 2′-(5"-triphosphoribosyl)-3′-dephospho-CoA and subsequent transfer to apo-citrate lyase with removal of pyrophosphate. In Escherichia coli, the two steps are catalyzed by CitG and CitX, respectively, and the corresponding genes are part of the citrate lyase gene cluster, citCDEFXG. In the homologous citCDEFG operon of Klebsiella pneumoniae, citX is missing. A search for K. pneumoniae citX led to the identification of a second genome region involved in citrate fermentation which comprised the citWX genes and the divergent citYZ genes. The citX gene was confirmed to encode holo-citrate lyase synthase, whereas citW was shown to encode a citrate carrier, the third one identified in this species. The citYZ genes were found to encode a two-component system consisting of the sensor kinase CitY and the response regulator CitZ. Remarkably, both proteins showed ≥40% sequence identity to the citrate-sensing CitA-CitB two-component system, which is essential for the induction of the citrate fermentation genes in K. pneumoniae. A citZ insertion mutant was able to grow anaerobically with citrate, indicating that CitZ is not essential for expression of citrate fermentation genes. CitX synthesis was induced to a basal level under anaerobic conditions, independent of citrate, CitB, and CitZ, and to maximal levels during anaerobic growth with citrate as the sole carbon source. Similar to the other citrate fermentation enzymes, CitX synthesis was apparently subject to catabolite repression.

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