Many Chromosomal Genes Modulate MarA-Mediated Multidrug Resistance in
            <i>Escherichia coli</i>

Ruiz, Cristian; Levy, Stuart B.

doi:10.1128/aac.01420-09

Cited by 61 publications

(57 citation statements)

References 46 publications

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“…The only readily predictable example was the transcriptional activator MarA, which we isolated from environments containing two quinolones (ciprofloxacin and ofloxacin), a tetracycline (penimepicycline), a macrolide (tylosin), and a mutagen (proflavine). MarA is known to mediate multidrug resistance by up-regulating the efflux system and down-regulating membrane permeability (32,33). In other cases, we found genes that had not previously been associated with resistance, including the biofilm modulation protein, Bdm, the small stress response protein, YcgZ, and the global regulator of transcription, CpdA (cAMP phosphodiesterase).…”

Section: Resultsmentioning

confidence: 72%

Artificial gene amplification reveals an abundance of promiscuous resistance determinants in Escherichia coli

Soo

Hanson‐Manful²,

Patrick³

2010

Proc. Natl. Acad. Sci. U.S.A.

112

110

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Duplicated genes provide an important raw material for adaptive evolution. However, the relationship between gene duplication and the emergence of new biochemical functions is complicated, and it has been difficult to quantify the likelihood of evolving novelty in any systematic manner. Here, we describe a comprehensive search for artificially amplified genes that are able to impart new phenotypes on Escherichia coli, provided their expression is up-regulated. We used a high-throughput, library-on-library strategy to screen for resistance to antibiotics and toxins. Cells containing a complete E. coli ORF library were exposed to 237 toxin-containing environments. From 86 of these environments, we identified a total of 115 cases where overexpressed ORFs imparted improved growth. Of the overexpressed ORFs that we tested, most conferred small but reproducible increases in minimum inhibitory concentration (≤16-fold) for their corresponding antibiotics. In many cases, proteins were acting promiscuously to impart resistance. In the absence of toxins, most strains bore no fitness cost associated with ORF overexpression. Our results show that even the genome of a nonpathogenic bacterium harbors a substantial reservoir of resistance genes, which can be readily accessed through overexpression mutations. During the growth of a population under selection, these mutations are most likely to be gene amplifications. Therefore, our work provides validation and biochemical insight into the innovation, amplification, and divergence model of gene evolution under continuous selection [Bergthorsson U, Andersson DI, Roth JR (2007) Proc Natl Acad Sci USA 104:17004-17009], and also illustrates the high frequency at which novel traits can evolve in bacterial populations.antibiotic resistance | evolutionary innovation | molecular evolution | protein promiscuity | phenotype microarray

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Section: Resultsmentioning

confidence: 72%

Artificial gene amplification reveals an abundance of promiscuous resistance determinants in Escherichia coli

Soo

Hanson‐Manful²,

Patrick³

2010

Proc. Natl. Acad. Sci. U.S.A.

112

110

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“…The major efflux pump in E. coli is AcrAB-TolC. Although the architecture, assembly, and function of AcrAB-TolC are well known (50,51), and the transcriptional control of the genes encoding AcrAB and TolC have been examined (46,(52)(53)(54)(55)(56), very little has been done to study posttranscriptional regulation. We investigated the role of Hfq-dependent sRNAs in the regulation of genes encoding the efflux pump.…”

Section: Discussionmentioning

confidence: 99%

Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters

Parker

Gottesman

2016

J Bacteriol

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Bacteria use multidrug efflux pumps to export drugs and toxic compounds out of the cell. One of the most important efflux pumps in Escherichia coli is the AcrAB-TolC system. Small regulatory RNAs (sRNAs) are known to be major posttranscriptional regulators that can enhance or repress translation by binding to the 5= untranslated region (UTR) of mRNA targets with the help of a chaperone protein, Hfq. In this study, we investigated the expression of acrA, acrB, and tolC translational fusions using 27 Hfq-dependent sRNAs overexpressed from plasmids. No significant sRNA regulation of acrA or acrB was detected. SdsR (also known as RyeB), an abundant and well-conserved stationary-phase sRNA, was found to repress the expression of tolC, the gene encoding the outer membrane protein of many multidrug resistance efflux pumps. This repression was shown to be by direct base pairing occurring upstream from the ribosomal binding site. SdsR overexpression and its regulation of tolC were found to reduce resistance to novobiocin and crystal violet. Our results suggest that additional targets for SdsR exist that contribute to increased antibiotic sensitivity and reduced biofilm formation. In an effort to identify phenotypes associated with single-copy SdsR and its regulation of tolC, the effect of a deletion of sdsR or mutations in tolC that should block SdsR pairing were investigated using a Biolog phenotypic microarray. However, no significant phenotypes were identified. Therefore, SdsR appears to modulate rather than act as a major regulator of its targets. IMPORTANCEAcrAB-TolC is a major efflux pump present in E. coli and Gram-negative bacteria used to export toxic compounds; the pump confers resistance to many antibiotics of unrelated classes. In this study, we found that SdsR, a small RNA expressed in stationary phase, repressed the expression of tolC, resulting in increased sensitivity to some antibiotics. This extends the findings of previous studies showing that sRNAs contribute to the regulation of many outer membrane proteins; manipulating or enhancing their action might help in sensitizing bacteria to antibiotics.

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“…Having a structure for a SPOR:glycan complex might facilitate the development of small-molecule inhibitors with therapeutic potential. In this context, it is worth noting that bacterial mutants lacking SPOR domain proteins are often sensitized to multiple antibiotics or are conditionally lethal (13,25,(74)(75)(76)(77), suggesting that these proteins might be exploited as targets for codrugs that improve the efficacy of existing antibiotics.…”

Section: Discussionmentioning

confidence: 99%

The SPOR Domain, a Widely Conserved Peptidoglycan Binding Domain That Targets Proteins to the Site of Cell Division

2017

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Sporulation-related repeat (SPOR) domains are small peptidoglycan (PG) binding domains found in thousands of bacterial proteins. The name "SPOR domain" stems from the fact that several early examples came from proteins involved in sporulation, but SPOR domain proteins are quite diverse and contribute to a variety of processes that involve remodeling of the PG sacculus, especially with respect to cell division. SPOR domains target proteins to the division site by binding to regions of PG devoid of stem peptides ("denuded" glycans), which in turn are enriched in septal PG by the intense, localized activity of cell wall amidases involved in daughter cell separation. This targeting mechanism sets SPOR domain proteins apart from most other septal ring proteins, which localize via protein-protein interactions. In addition to SPOR domains, bacteria contain several other PG-binding domains that can exploit features of the cell wall to target proteins to specific subcellular sites.

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Many Chromosomal Genes Modulate MarA-Mediated Multidrug Resistance in Escherichia coli

Cited by 61 publications

References 46 publications

Artificial gene amplification reveals an abundance of promiscuous resistance determinants in Escherichia coli

Artificial gene amplification reveals an abundance of promiscuous resistance determinants in Escherichia coli

Small RNA Regulation of TolC, the Outer Membrane Component of Bacterial Multidrug Transporters

The SPOR Domain, a Widely Conserved Peptidoglycan Binding Domain That Targets Proteins to the Site of Cell Division

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