Identification of a novel plasmid-encoded dihydrofolate reductase mediating high-level resistance to trimethoprim

1988 ◽  
Vol 22 (4) ◽  
pp. 429-435 ◽  
Author(s):  
B. A. Wylie ◽  
S. G. B. Amyes ◽  
H.-K. Young ◽  
H. J. Koornhof
Keyword(s):  
Dihydrofolate Reductase ◽  
High Level ◽  
Level Resistance

scholarly journals Trimethoprim-resistant mutants ofE. coliK12: preliminary genetic mapping

1975 ◽  
Vol 25 (3) ◽  
pp. 207-214 ◽  
Author(s):  
A. S. Breeze ◽  
P. Sims ◽  
K. A. Stacey
Keyword(s):  
Genetic Mapping ◽  
Structural Gene ◽  
Dihydrofolate Reductase ◽  
Bacteriophage P1 ◽  
E Coli ◽  
Resistant Mutants ◽  
High Level ◽  
Increased Activity ◽  
Level Resistance ◽  
Target Enzyme

SUMMARYTrimethoprim-resistant mutants ofE. coliK12 have been isolated by-serial subculture in progressively higher concentrations of trimethoprim. High-level resistance depends on the accumulation of several mutational changes. Transduction with bacteriophage P1 has shown that all the mutations involved in resistance are associated with a locus, to be calledtmr, betweenpyr AandpdxAand closely linked topdxA. Resistance is accompanied by, and presumably due to, an increased activity of the target enzyme, dihydrofolate reductase. Thetmrlocus may include the structural gene for dihydrofolate reductase but the only mutations that have so far been observed are concerned with regulation.

Emergence of the trimethoprim resistance gene dfrD in Listeria monocytogenes BM4293.

1997 ◽  
Vol 41 (5) ◽  
pp. 1134-1136 ◽  
Author(s):  
E Charpentier ◽  
P Courvalin
Keyword(s):  
Listeria Monocytogenes ◽  
Resistance Gene ◽  
Dihydrofolate Reductase ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Staphylococcus Haemolyticus ◽  
High Level ◽  
Level Resistance

The sequence of the trimethoprim resistance gene of the 3.7-kb plasmid (pIP823) that confers high-level resistance (MIC, 1,024 microg/ml) to Listeria monocytogenes BM4293 was determined. The gene was identical to dfrD recently detected in Staphylococcus haemolyticus MUR313. The corresponding protein, S2DHFR, represents the second class of high-level trimethoprim-resistant dihydrofolate reductase identified in gram-positive bacteria. We propose that trimethoprim resistance in L. monocytogenes BM4293 could originate in staphylococci.

scholarly journals The distribution of the DHFR genes in trimethoprim-resistant urinary tract isolates from Taiwan

1992 ◽  
Vol 109 (3) ◽  
pp. 453-462 ◽  
Author(s):  
Lin-Li Chang ◽  
Shui-Feng Chang ◽  
Teh-Yuan Chow ◽  
Wen-Jeng Wu ◽  
Jong-Chou Chang
Keyword(s):  
Escherichia Coli ◽  
Dihydrofolate Reductase ◽  
Type I ◽  
Type Ii ◽  
Colony Hybridization ◽  
Resistant Strains ◽  
High Level ◽  
Type V ◽  
Urinary Isolates ◽  
Level Resistance

SUMMARYBetween July 1987 and June 1989, 1054 urinary isolates of enterobacteria from Kaohsiung, Taiwan were studied for their trimethoprim resistance. Trimethoprim resistance was defined as MIC greater than 4 μg/ml and high-level resistance by MIC greater than 1000 μg/ml. The incidence of trimethoprim resistance increased from 33·6% in 1987 to 42·1% in 1989. Among the resistant strains studied, 90% were resistant to high levels of trimethoprim. An increase in the proportion of resistant strains (33·9–46·3%) exhibiting high-level non-transferable trimethoprim resistance was noted. The distribution of the dihydrofolate reductase (DHFR) genes by colony hybridization in 374 trimethoprim-resistant isolates revealed the presence of type I and type V DHFR genes in most of these isolates (45·4% and 10·4% respectively). Type I was predominant inEscherichia coliwhereas type V was frequently seen inEnterobacterspp. None showed homology with the type II and type III DHFR probe DNA. In addition, transposon Tn7 was present in 7·8% of 374 trimethoprim-resistant enterobacteria.

scholarly journals Transmission and Cross-Mating of High-Level Resistance Plasmodium falciparum Dihydrofolate Reductase Haplotypes in The Gambia

2010 ◽  
Vol 82 (4) ◽  
pp. 535-541 ◽  
Author(s):  
Amani Kheir ◽  
Yagut Akbarova ◽  
Salma Al-Saai ◽  
Göte Swedberg ◽  
Hamza A. Babiker ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dihydrofolate Reductase ◽  
The Gambia ◽  
High Level ◽  
Level Resistance

The Chemistry of Drugs to Treat Candida albicans

2019 ◽  
Vol 19 (28) ◽  
pp. 2554-2566 ◽  
Author(s):  
Aurelio Ortiz ◽  
Estibaliz Sansinenea
Keyword(s):  
Candida Species ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Drug Classes ◽  
Life Threatening ◽  
Antifungal Substances ◽  
High Level ◽  
Systemic Infections ◽  
New Compounds ◽  
Level Resistance

Background:: Candida species are in various parts of the human body as commensals. However, they can cause local mucosal infections and, sometimes, systemic infections in which Candida species can spread to all major organs and colonize them. Objective:: For the effective treatment of the mucosal infections and systemic life-threatening fungal diseases, a considerably large number of antifungal drugs have been developed and used for clinical purposes that comprise agents from four main drug classes: the polyenes, azoles, echinocandins, and antimetabolites. Method: : The synthesis of some of these drugs is available, allowing synthetic modification of the molecules to improve the biological activity against Candida species. The synthetic methodology for each compound is reviewed. Results: : The use of these compounds has caused a high-level resistance against these drugs, and therefore, new antifungal substances have been described in the last years. The organic synthesis of the known and new compounds is reported. Conclusion: : This article summarizes the chemistry of the existing agents, both the old drugs and new drugs, in the treatment of infections due to C. albicans, including the synthesis of the existing drugs.

scholarly journals Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis

2020 ◽  
Vol 65 (1) ◽  
pp. e01948-20
Author(s):  
Dalin Rifat ◽  
Si-Yang Li ◽  
Thomas Ioerger ◽  
Keshav Shah ◽  
Jean-Philippe Lanoix ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Clinical Evidence ◽  
Clinical Samples ◽  
Loss Of Function ◽  
Wild Type ◽  
Content Type ◽  
Solid Media ◽  
High Level ◽  
Level Resistance

ABSTRACTThe nitroimidazole prodrugs delamanid and pretomanid comprise one of only two new antimicrobial classes approved to treat tuberculosis (TB) in 50 years. Prior in vitro studies suggest a relatively low barrier to nitroimidazole resistance in Mycobacterium tuberculosis, but clinical evidence is limited to date. We selected pretomanid-resistant M. tuberculosis mutants in two mouse models of TB using a range of pretomanid doses. The frequency of spontaneous resistance was approximately 10−5 CFU. Whole-genome sequencing of 161 resistant isolates from 47 mice revealed 99 unique mutations, of which 91% occurred in 1 of 5 genes previously associated with nitroimidazole activation and resistance, namely, fbiC (56%), fbiA (15%), ddn (12%), fgd (4%), and fbiB (4%). Nearly all mutations were unique to a single mouse and not previously identified. The remaining 9% of resistant mutants harbored mutations in Rv2983 (fbiD), a gene not previously associated with nitroimidazole resistance but recently shown to be a guanylyltransferase necessary for cofactor F420 synthesis. Most mutants exhibited high-level resistance to pretomanid and delamanid, although Rv2983 and fbiB mutants exhibited high-level pretomanid resistance but relatively small changes in delamanid susceptibility. Complementing an Rv2983 mutant with wild-type Rv2983 restored susceptibility to pretomanid and delamanid. By quantifying intracellular F420 and its precursor Fo in overexpressing and loss-of-function mutants, we provide further evidence that Rv2983 is necessary for F420 biosynthesis. Finally, Rv2983 mutants and other F420H2-deficient mutants displayed hypersusceptibility to some antibiotics and to concentrations of malachite green found in solid media used to isolate and propagate mycobacteria from clinical samples.

scholarly journals Molecular pathways to high-level azithromycin resistance in Neisseria gonorrhoeae

2021 ◽  
Author(s):  
J G E Laumen ◽  
S S Manoharan-Basil ◽  
E Verhoeven ◽  
S Abdellati ◽  
I De Baetselier ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Ribosomal Proteins ◽  
Efflux Pump ◽  
23S Rrna ◽  
Rrna Gene ◽  
23S Rrna Gene ◽  
Evolution Of Resistance ◽  
High Level ◽  
Azithromycin Resistance ◽  
Level Resistance

Abstract Background The prevalence of azithromycin resistance in Neisseria gonorrhoeae is increasing in numerous populations worldwide. Objectives To characterize the genetic pathways leading to high-level azithromycin resistance. Methods A customized morbidostat was used to subject two N. gonorrhoeae reference strains (WHO-F and WHO-X) to dynamically sustained azithromycin pressure. We tracked stepwise evolution of resistance by whole genome sequencing. Results Within 26 days, all cultures evolved high-level azithromycin resistance. Typically, the first step towards resistance was found in transitory mutations in genes rplD, rplV and rpmH (encoding the ribosomal proteins L4, L22 and L34 respectively), followed by mutations in the MtrCDE-encoded efflux pump and the 23S rRNA gene. Low- to high-level resistance was associated with mutations in the ribosomal proteins and MtrCDE efflux pump. However, high-level resistance was consistently associated with mutations in the 23S ribosomal RNA, mainly the well-known A2059G and C2611T mutations, but also at position A2058G. Conclusions This study enabled us to track previously reported mutations and identify novel mutations in ribosomal proteins (L4, L22 and L34) that may play a role in the genesis of azithromycin resistance in N. gonorrhoeae.

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