scholarly journals Resistance to pentamidine is mediated by AdeAB, regulated by AdeRS, and influenced by growth conditions inAcinetobacter baumanniiATCC 17978

2018 ◽  
Author(s):  
Felise G. Adams ◽  
Uwe H. Stroeher ◽  
Karl A. Hassan ◽  
Shashikanth Marri ◽  
Melissa H. Brown
Keyword(s):  
Signal Transduction ◽  
Antimicrobial Resistance ◽  
Carbon Sources ◽  
Growth Conditions ◽  
Multidrug Efflux ◽  
Intrinsic Resistance ◽  
Multidrug Efflux Pumps ◽  
Two Component ◽  
Two Component Signal Transduction

AbstractIn recent years, effective treatment of infections caused byAcinetobacter baumanniihas become challenging due to the ability of the bacterium to acquire or up-regulate antimicrobial resistance determinants. Two component signal transduction systems are known to regulate expression of virulence factors including multidrug efflux pumps. Here, we investigated the role of the AdeRS two component signal transduction system in regulating the AdeAB efflux system, determined whether AdeA and/or AdeB can individually confer antimicrobial resistance, and explored the interplay between pentamidine resistance and growth conditions inA. baumanniiATCC 17978. Results identified that deletion ofadeRSaffected resistance towards chlorhexidine and 4’,6-diamidino-2-phenylindole dihydrochloride, two previously defined AdeABC substrates, and also identified an 8-fold decrease in resistance to pentamidine. Examination of ΔadeA, ΔadeBand ΔadeABcells augmented results seen for ΔadeRSand identified a set of dicationic AdeAB substrates. RNA-sequencing of ΔadeRSrevealed transcription of 290 genes were ≥2-fold altered compared to the wildtype. Pentamidine shock significantly increasedadeAexpression in the wildtype, but decreased it in ΔadeRS, implying that AdeRS activatesadeABtranscription in ATCC 17978. Investigation under multiple growth conditions, including the use of Biolog phenotypic microarrays, revealed resistance to pentamidine in ATCC 17978 and mutants could be altered by bioavailability of iron or utilization of different carbon sources. In conclusion, the results of this study provide evidence that AdeAB in ATCC 17978 can confer intrinsic resistance to a subset of dicationic compounds and in particular, resistance to pentamidine can be significantly altered depending on the growth conditions.

scholarly journals Characterization of Posttranslationally Modified Multidrug Efflux Pumps Reveals an Unexpected Link between Glycosylation and Antimicrobial Resistance

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Sherif Abouelhadid ◽  
John Raynes ◽  
Tam Bui ◽  
Jon Cuccui ◽  
Brendan W. Wren
Keyword(s):  
Antimicrobial Resistance ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Gram Negative ◽  
Content Type ◽  
Multidrug Efflux Pumps ◽  
Pump Activity

ABSTRACT The substantial rise in multidrug-resistant bacterial infections is a current global imperative. Cumulative efforts to characterize antimicrobial resistance in bacteria has demonstrated the spread of six families of multidrug efflux pumps, of which resistance-nodulation-cell division (RND) is the major mechanism of multidrug resistance in Gram-negative bacteria. RND is composed of a tripartite protein assembly and confers resistance to a range of unrelated compounds. In the major enteric pathogen Campylobacter jejuni, the three protein components of RND are posttranslationally modified with N-linked glycans. The direct role of N-linked glycans in C. jejuni and other bacteria has long been elusive. Here, we present the first detailed account of the role of N-linked glycans and the link between N-glycosylation and antimicrobial resistance in C. jejuni. We demonstrate the multifunctional role of N-linked glycans in enhancing protein thermostability, stabilizing protein complexes and the promotion of protein-protein interaction, thus mediating antimicrobial resistance via enhancing multidrug efflux pump activity. This affirms that glycosylation is critical for multidrug efflux pump assembly. We present a generalized strategy that could be used to investigate general glycosylation system in Campylobacter genus and a potential target to develop antimicrobials against multidrug-resistant pathogens. IMPORTANCE Nearly all bacterial species have at least a single glycosylation system, but the direct effects of these posttranslational protein modifications are unresolved. Glycoproteome-wide analysis of several bacterial pathogens has revealed general glycan modifications of virulence factors and protein assemblies. Using Campylobacter jejuni as a model organism, we have studied the role of general N-linked glycans in the multidrug efflux pump commonly found in Gram-negative bacteria. We show, for the first time, the direct link between N-linked glycans and multidrug efflux pump activity. At the protein level, we demonstrate that N-linked glycans play a role in enhancing protein thermostability and mediating the assembly of the multidrug efflux pump to promote antimicrobial resistance, highlighting the importance of this posttranslational modification in bacterial physiology. Similar roles for glycans are expected to be found in other Gram-negative pathogens that possess general protein glycosylation systems.

scholarly journals Role of functionality in two-component signal transduction: A stochastic study

2014 ◽  
Vol 89 (3) ◽  
Author(s):  
Alok Kumar Maity ◽  
Arnab Bandyopadhyay ◽  
Pinaki Chaudhury ◽  
Suman K. Banik
Keyword(s):  
Signal Transduction ◽  
Two Component ◽  
Two Component Signal Transduction
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