Protein Kinase G Is Required for Intrinsic Antibiotic Resistance in Mycobacteria

Wolff, Kerstin; Nguyen, Hoa; Cartabuke, Richard H.; Singh, Ajay Vir; Ogwang, Sam; Nguyen, Liem

doi:10.1128/aac.00012-09

Cited by 58 publications

(69 citation statements)

References 29 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DCGen3002-1 encoded a protein similar to phosphomannomutase and DCKan30A29 encoded a protein similar to nucleotide sugar dehydrogenase, both of which are responsible for alginate polymerization and the resultant alginate layer would cause a mucoid phenotype and provide a protective barrier against host immune defenses and antibiotics (May et al, 1991;Naught et al, 2002). DCKan30A03 encoded 2-oxoglutarate dehydrogenase is involved in glutamine utilization and could reduce cell wall hydrophobicity, which has previously been reported to be important for multiple antibiotic resistance (Wolff et al, 2009). Efflux pump mediated resistance was found in ABC transporter like protein encoded DCKan30A31-2.…”

Section: Aminoglycoside Resistancementioning

confidence: 99%

Functional metagenomic characterization of antibiotic resistance genes in agricultural soils from China

Wei

et al. 2014

Environment International

151

View full text Add to dashboard Cite

Section: Aminoglycoside Resistancementioning

confidence: 99%

Functional metagenomic characterization of antibiotic resistance genes in agricultural soils from China

Wei

et al. 2014

Environment International

151

View full text Add to dashboard Cite

“…The loss of pknG function has been previously implicated in the increased sensitivity of M.smegmatis to multiple antibiotics (65) , perhaps due to a decrease in cell wall hydrophobicity. In addition, quantitative RT-PCR (Figure 4) revealed that icl1 (encoding isocitrate lyase, part of the glyoxylate bypass), narX (involved in nitrate reduction), and tgs1 (a triacylglycerol synthase) were all NRP2 and INH-responsive.…”

Section: Use Of Transcriptional Profiling To Screen For Nrp and Inh-rmentioning

confidence: 99%

Examining the Basis of Isoniazid Tolerance in Nonreplicating Mycobacterium Tuberculosis Using Transcriptional Profiling

et al. 2010

View full text Add to dashboard Cite

Background: Understanding how growth state influences Mycobacterium tuberculosis responses to antibiotic exposure provides a window into drug action during patient chemotherapy. In this article, we describe the transcriptional programs mediated by isoniazid (INH) during the transition from log-phase to nonreplicating bacilli, from INH-sensitive to INH-tolerant bacilli respectively, using the Wayne model. Results: INH treatment did not elicit a transcriptional response from nonreplicating bacteria under microarophilic conditions (NRP2), unlike the induction of a robust and well-characterized INH signature in log-phase bacilli. Conclusion: The differential regulation (between drug-free NRP2 and log-phase bacilli) of genes directly implicated in INH resistance could not account for the abrogation of INH killing in nongrowing bacilli. Thus, factors affecting the requirement for mycolic acids and the redox status of bacilli are likely responsible for the reduction in INH efficacy. We speculate on additional mechanisms revealed by transcriptome analysis that might account for INH tolerance.

show abstract

“…Minimum inhibitory concentrations (MICs) of selected mutants to antifolates were determined by serial dilution assays (see below). Mapping of transposon insertion sites in the mutants by using an arbitrary PCR method was carried out as described previously (16,18).…”

mentioning

confidence: 99%

“…The entire open reading frame of M. smegmatis msmeg_5472 was deleted using the recombineering method as described previously (18). The 616-bp DNA region upstream of msmeg_5472 was PCR-amplified using primers fuel-Del1 and fuel-Del2 (supplemental Table S2).…”

mentioning

confidence: 99%

“…These DNA arms were cloned into pYUB854 (22) flanking the built-in hygromycin cassette to create pVN842. The ⌬msmeg5472::⍀hyg linear allelic exchange substrate was removed from pVN842 by SpeI/KpnI digestion and used to transform M. smegmatis mc 2 155 cells induced to express the recombineering system from pVN701B (18). Plasmid pVN701B was later removed from ⌬msmeg5472 mutant as described previously (18).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Bacterial Conversion of Folinic Acid Is Required for Antifolate Resistance

Ogwang

Nguyen

Sherman

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Antifolates, which are among the first antimicrobial agents invented, inhibit cell growth by creating an intracellular state of folate deficiency. Clinical resistance to antifolates has been mainly attributed to mutations that alter structure or expression of enzymes involved in de novo folate synthesis. We identified a Mycobacterium smegmatis mutant, named FUEL (which stands for folate utilization enzyme for leucovorin), that is hypersusceptible to antifolates. Chemical complementation indicated that FUEL is unable to metabolize folinic acid (also known as leucovorin or 5-formyltetrahydrofolate), whose metabolic function remains unknown. Targeted mutagenesis, genetic complementation, and biochemical studies showed that FUEL lacks 5,10-methenyltetrahydrofolate synthase (MTHFS; also called 5-formyltetrahydrofolate cyclo-ligase; EC 6.3.3.2) activity responsible for the only ATP-dependent, irreversible conversion of folinic acid to 5,10-methenyltetrahydrofolate. In trans expression of active MTHFS proteins from bacteria or human restored both antifolate resistance and folinic acid utilization to FUEL. Absence of MTHFS resulted in marked cellular accumulation of polyglutamylated species of folinic acid. Importantly, MTHFS also affected M. smegmatis utilization of monoglutamylated 5-methyltetrahydrofolate exogenously added to the medium. Likewise, Escherichia coli mutants lacking MTHFS became susceptible to antifolates. These results indicate that folinic acid conversion by MTHFS is required for bacterial intrinsic antifolate resistance and folate homeostatic control. This novel mechanism of antimicrobial antifolate resistance might be targeted to sensitize bacterial pathogens to classical antifolates.

show abstract

Protein Kinase G Is Required for Intrinsic Antibiotic Resistance in Mycobacteria

Cited by 58 publications

References 29 publications

Functional metagenomic characterization of antibiotic resistance genes in agricultural soils from China

Functional metagenomic characterization of antibiotic resistance genes in agricultural soils from China

Examining the Basis of Isoniazid Tolerance in Nonreplicating Mycobacterium Tuberculosis Using Transcriptional Profiling

Bacterial Conversion of Folinic Acid Is Required for Antifolate Resistance

Contact Info

Product

Resources

About