scholarly journals Mutators drive evolution of multi-resistance to antibiotics

2019 ◽  
Author(s):  
Danna R. Gifford ◽  
Ernesto Berríos-Caro ◽  
Christine Joerres ◽  
Tobias Galla ◽  
Christopher G. Knight
Keyword(s):  
Drug Resistance ◽  
Combination Therapy ◽  
Antibiotic Treatment ◽  
Multi Drug Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Single Drug ◽  
Drug Treatments ◽  
K 12 ◽  
Sequential Acquisition

AbstractCombination therapy aims to prevent growth of organisms not resistant to all component drugs, making it an obvious strategy for countering the global rise of multi-drug resistance. However, success relies on preventing resistance from arising to all component drugs before full inhibition is reached during treatment. Here, we investigated whether bacterial populations can overcome combination therapy by evolving ‘multi-resistance’, i.e. independent resistance mutations to multiple drugs, during single-drug and combination antibiotic treatment. Using both experimental evolution and in silico stochastic simulations, we studied resistance evolution in a common laboratory strain of bacteria (Escherichia coli K-12 BW25113). Populations were exposed to either single-drug or combination treatments involving rifampicin and nalidixic acid, with concentrations increasing through time. For wild-type populations, multi-resistance was not detected in any of the experimental populations, and simulations predict its evolution should be rare. However, populations comprising mixtures of wild-type and ‘mutator’ strains were readily capable of evolving multi-resistance. Increasing the initial frequency of mutators resulted in a higher proportion of populations evolving multi-resistance. Experiments and simulations produced the same qualitative-and in many cases, quantitative-insights about the association between resistance, mutators and antibiotic treatment. In particular, both approaches demonstrated that multi-resistance can arise through sequential acquisition of independent resistance mutations, without a need to invoke multi-drug resistance mechanisms. Crucially, we found multi-resistance evolved even when not directly favoured by natural selection, i.e. under single-drug treatments. Simulations revealed this resulted from elevated mutation supply caused by genetic hitch-hiking of the mutator allele on single-drug resistant backgrounds. Our results suggest that combination therapy does not necessarily prevent sequential acquisition of multiple drug resistances via spontaneous mutation when mutators are present. Indeed both combination and single-drug treatments actively promoted multi-resistance, meaning that combination therapy will not be a panacea for the antibiotic resistance crisis.

scholarly journals Stenotrophomonas Maltophilia Peritonitis in a Child: Case Report and Review of Literature

2020 ◽  
Author(s):  
Demet Alaygut ◽  
Caner Alparslan ◽  
Serdar Sarıtaş ◽  
Elif Perihan Öncel ◽  
Önder Yavaşcan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Peritoneal Dialysis ◽  
Case Report ◽  
Antibiotic Treatment ◽  
Stenotrophomonas Maltophilia ◽  
Multi Drug Resistance ◽  
Review Of Literature ◽  
Dysplastic Kidney ◽  
Success Of Treatment

Stenotrophomonas maltophilia peritonitis has been only occasionally reported in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Because this microorganism has multi-drug resistance, its treatment is hard and long-term. The treatment might not be successful despite all the efforts and the process of peritoneal dialysis, and may terminate with loss of the catheter. In the present paper, S. maltophilia peritonitis developed in a 6-year-old girl patient, who underwent peritoneal dialysis due to bilateral dysplastic kidney, suffered from episodes of peritonitis frequently and required hospitalization, was presented with literature data. Even though the case received multiple antibiotic treatment and underwent endoluminal brushing (EB), the success of treatment could not be achieved. To the best of our knowledge, this patient is the youngest case in the literature.

scholarly journals Polymorphism Analysis of pfmdr1 Gene in Plasmodium falciparum Isolates 11 Years Post-adoption of Artemisinin-based Combination Therapy in Saudi Arabia

2021 ◽  
Author(s):  
Hesham M. Al-Mekhlafi ◽  
Aymen M. Madkhali ◽  
Ahmed A. Abdulhaq ◽  
Wahib M. Atroosh ◽  
Ahmad Hassn Ghzwani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Saudi Arabia ◽  
Combination Therapy ◽  
Point Mutations ◽  
Multi Drug Resistance ◽  
Polymorphism Analysis ◽  
Wild Allele ◽  
High Prevalence ◽  
Parasitaemia Level

Abstract A total of 227 Plasmodium falciparum isolates from Jazan region, southwestern Saudi Arabia were amplified for the P. falciparum multi-drug resistance 1 (pfmdr1) gene to detect point mutations 11 years after the introduction of artemisinin-based combination therapy (ACT) in Saudi Arabia. The pfmdr1 86Y mutation was found in 11.5% (26/227) of the isolates while the N86 wild allele was detected in 88.5%. Moreover, 184F point mutations dominated (86.3%) the instances of pfmdr1 polymorphism while no mutation was observed at codons 1034, 1042 and 1246. Three pfmdr1 haplotypes were identified, NFSND (74.9%), NYSND (13.7%) and YFSND (11.4%). Associations of the prevalence of 86Y mutation and YFSND haplotype with participants’ nationality, residency and parasitaemia level were found to be significant (P < 0.05). The findings revealed significant decline in the prevalence of the pfmdr1 86Y mutation in P. falciparum isolates from Jazan region over a decade after the implementation of ACT treatment. Moreover, the high prevalence of the NFSND haplotype might be indicative of the potential emergence of CQ-sensitive but artemether-lumefantrine-resistant P. falciparum strains since the adoption of ACT. Therefore, continuous monitoring of the molecular markers of antimalarial drug resistance in Jazan region is highly recommended.

Trade-offs with stability modulate innate and mutationally acquired drug resistance in bacterial dihydrofolate reductase enzymes

2018 ◽  
Vol 475 (12) ◽  
pp. 2107-2125 ◽  
Author(s):  
Nishad Matange ◽  
Swapnil Bodkhe ◽  
Maitri Patel ◽  
Pooja Shah
Keyword(s):  
Drug Resistance ◽  
Structural Stability ◽  
Dihydrofolate Reductase ◽  
Mutational Analysis ◽  
Hydrophobic Interactions ◽  
Wild Type ◽  
Resistance Mutations ◽  
Acquired Drug Resistance ◽  
Trade Offs ◽  
And Function

Structural stability is a major constraint on the evolution of protein sequences. However, under strong directional selection, mutations that confer novel phenotypes but compromise structural stability of proteins may be permissible. During the evolution of antibiotic resistance, mutations that confer drug resistance often have pleiotropic effects on the structure and function of antibiotic-target proteins, usually essential metabolic enzymes. In the present study, we show that trimethoprim (TMP)-resistant alleles of dihydrofolate reductase from Escherichia coli (EcDHFR) harboring the Trp30Gly, Trp30Arg or Trp30Cys mutations are significantly less stable than the wild-type, making them prone to aggregation and proteolysis. This destabilization is associated with a lower expression level, resulting in a fitness cost and negative epistasis with other TMP-resistant mutations in EcDHFR. Using structure-based mutational analysis, we show that perturbation of critical stabilizing hydrophobic interactions in wild-type EcDHFR enzyme explains the phenotypes of Trp30 mutants. Surprisingly, though crucial for the stability of EcDHFR, significant sequence variation is found at this site among bacterial dihydrofolate reductases (DHFRs). Mutational and computational analyses in EcDHFR and in DHFR enzymes from Staphylococcus aureus and Mycobacterium tuberculosis demonstrate that natural variation at this site and its interacting hydrophobic residues modulates TMP resistance in other bacterial DHFRs as well, and may explain the different susceptibilities of bacterial pathogens to TMP. Our study demonstrates that trade-offs between structural stability and function can influence innate drug resistance as well as the potential for mutationally acquired drug resistance of an enzyme.

scholarly journals Combined Drug Resistance Mutations Substantially Enhance Enzyme Production inPaenibacillus agaridevorans

2018 ◽  
Vol 200 (17) ◽  
Author(s):  
Kazumi Funane ◽  
Yukinori Tanaka ◽  
Takeshi Hosaka ◽  
Kiriko Murakami ◽  
Takatsugu Miyazaki ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Enzyme Production ◽  
Scale Production ◽  
Wild Type ◽  
Resistance Mutations ◽  
Triple Mutant ◽  
Content Type ◽  
Wide Applicability ◽  
Drug Resistance Mutations ◽  
Industrial Enzyme

ABSTRACTThis study shows that sequential introduction of drug resistance mutations substantially increased enzyme production inPaenibacillus agaridevorans. The triple mutant YT478 (rsmGGln225→stop codon,rpsLK56R, andrpoBR485H), generated by screening for resistance to streptomycin and rifampin, expressed a 1,100-fold-larger amount of the extracellular enzyme cycloisomaltooligosaccharide glucanotransferase (CITase) than the wild-type strain. These mutants were characterized by higher intracellularS-adenosylmethionine concentrations during exponential phase and enhanced protein synthesis activity during stationary phase. Surprisingly, the maximal expression of CITase mRNA was similar in the wild-type and triple mutant strains, but the mutant showed greater CITase mRNA expression throughout the growth curve, resulting in enzyme overproduction. A metabolome analysis showed that the triple mutant YT478 had higher levels of nucleic acids and glycolysis metabolites than the wild type, indicating that YT478 mutant cells were activated. The production of CITase by the triple mutant was further enhanced by introducing a mutation conferring resistance to the rare earth element, scandium. This combined drug resistance mutation method also effectively enhanced the production of amylases, proteases, and agarases byP. agaridevoransandStreptomyces coelicolor. This method also activated the silent or weak expression of theP. agaridevoransCITase gene, as shown by comparisons of the CITase gene loci ofP. agaridevoransT-3040 and another cycloisomaltooligosaccharide-producing bacterium,Paenibacillussp. strain 598K. The simplicity and wide applicability of this method should facilitate not only industrial enzyme production but also the identification of dormant enzymes by activating the expression of silent or weakly expressed genes.IMPORTANCEEnzyme use has become more widespread in industry. This study evaluated the molecular basis and effectiveness of ribosome engineering in markedly enhancing enzyme production (>1,000-fold). This method, due to its simplicity, wide applicability, and scalability for large-scale production, should facilitate not only industrial enzyme production but also the identification of novel enzymes, because microorganisms contain many silent or weakly expressed genes which encode novel antibiotics or enzymes. Furthermore, this study provides a new mechanism for strain improvement, with a consistent rather than transient high expression of the key gene(s) involved in enzyme production.

scholarly journals Polymorphism analysis of pfmdr1 gene in Plasmodium falciparum isolates 11 years post-adoption of artemisinin-based combination therapy in Saudi Arabia

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Hesham M. Al-Mekhlafi ◽  
Aymen M. Madkhali ◽  
Ahmed A. Abdulhaq ◽  
Wahib M. Atroosh ◽  
Ahmad Hassn Ghzwani ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Saudi Arabia ◽  
Combination Therapy ◽  
Point Mutations ◽  
Multi Drug Resistance ◽  
Polymorphism Analysis ◽  
Wild Allele ◽  
High Prevalence ◽  
Parasitaemia Level

AbstractA total of 227 Plasmodium falciparum isolates from Jazan region, southwestern Saudi Arabia were amplified for the P. falciparum multi-drug resistance 1 (pfmdr1) gene to detect point mutations 11 years after the introduction of artemisinin-based combination therapy (ACT) in Saudi Arabia. The pfmdr1 86Y mutation was found in 11.5% (26/227) of the isolates while the N86 wild allele was detected in 88.5%. Moreover, 184F point mutations dominated (86.3%) the instances of pfmdr1 polymorphism while no mutation was observed at codons 1034, 1042 and 1246. Three pfmdr1 haplotypes were identified, NFSND (74.9%), NYSND (13.7%) and YFSND (11.4%). Associations of the prevalence of 86Y mutation and YFSND haplotype with participants’ nationality, residency and parasitaemia level were found to be significant (P < 0.05). The findings revealed significant decline in the prevalence of the pfmdr1 86Y mutation in P. falciparum isolates from Jazan region over a decade after the implementation of ACT treatment. Moreover, the high prevalence of the NFSND haplotype might be indicative of the potential emergence of CQ-sensitive but artemether-lumefantrine-resistant P. falciparum strains since the adoption of ACT. Therefore, continuous monitoring of the molecular markers of antimalarial drug resistance in Jazan region is highly recommended.

scholarly journals Competition delays multi-drug resistance evolution during combination therapy

2021 ◽  
Vol 509 ◽  
pp. 110524
Author(s):  
Ernesto Berríos-Caro ◽  
Danna R. Gifford ◽  
Tobias Galla
Keyword(s):  
Drug Resistance ◽  
Combination Therapy ◽  
Multi Drug Resistance ◽  
Resistance Evolution

scholarly journals Effects of Drug Resistance Mutations L100I and V106A on the Binding of Pyrrolobenzoxazepinone Nonnucleoside Inhibitors to the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Catalytic Complex

2004 ◽  
Vol 48 (5) ◽  
pp. 1570-1580 ◽  
Author(s):  
Giada A. Locatelli ◽  
Giuseppe Campiani ◽  
Reynel Cancio ◽  
Elena Morelli ◽  
Anna Ramunno ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Wild Type ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We have previously described a novel class of nonnucleoside reverse transcriptase (RT) inhibitors, the pyrrolobenzoxazepinone (PBO) and the pyridopyrrolooxazepinone (PPO) derivatives, which were effective inhibitors of human immunodeficiency virus type 1 (HIV-1) RT, either wild type or carrying known drug resistance mutations (G. Campiani et al., J. Med. Chem. 42:4462-4470, 1999). The lead compound of the PPO class, (R)-(−)-PPO464, was shown to selectively target the ternary complex formed by the viral RT with its substrates nucleic acid and nucleotide (G. Maga et al., J. Biol. Chem. 276:44653-44662, 2001). In order to better understand the structural basis for this selectivity, we exploited some PBO analogs characterized by various substituents at C-3 and by different inhibition potencies and drug resistance profiles, and we studied their interaction with HIV-1 RT wild type or carrying the drug resistance mutations L100I and V106A. Our kinetic and thermodynamic analyses showed that the formation of the complex between the enzyme and the nucleotide increased the inhibition potency of the compound PBO354 and shifted the free energy (energy of activation, ΔG#) for inhibitor binding toward more negative values. The V106A mutation conferred resistance to PBO 354 by increasing its dissociation rate from the enzyme, whereas the L100I mutation mainly decreased the association rate. This latter mutation also caused a severe reduction in the catalytic efficiency of the RT. These results provide a correlation between the efficiency of nucleotide utilization by RT and its resistance to PBO inhibition.

scholarly journals Prevalence of pfk13 and pfmdr1 polymorphisms in Bounkiling, Southern Senegal

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0249357
Author(s):  
Ambroise Ahouidi ◽  
Rafael Oliveira ◽  
Lis Lobo ◽  
Cyrille Diedhiou ◽  
Souleymane Mboup ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Pcr Amplification ◽  
Parasite Clearance ◽  
Dried Blood Spots ◽  
Multi Drug Resistance ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
Multidrug Resistance Gene ◽  
Filter Papers

Background Delayed Plasmodium falciparum parasite clearance has been associated with Single Nucleotide Polymorphisms (SNPs) in the kelch protein propeller domain (coded by pfk13 gene). SNPs in the Plasmodium falciparum multidrug resistance gene 1 (pfmdr1) are associated with multi-drug resistance including the combination artemether-lumefantrine. To our knowledge, this is the first work providing information on the prevalence of k13-propeller and pfmdr1 mutations from Sédhiou, a region in the south of Senegal. Methods 147 dried blood spots on filter papers were collected from symptomatic patients attending a hospital located in Bounkiling City, Sédhiou Region, Southern Senegal. All samples were collected between 2015–2017 during the malaria transmission season. Specific regions of the gene pfk13 and pfmdr1 were analyzed using PCR amplification and Sanger sequencing. Results The majority of parasites (92.9%) harboured the pfk13 wild type sequence and 6 samples harboured synonymous changes. Regarding pfmdr1, wild-type alleles represented the majority except at codon 184. Overall, prevalence of 86Y was 11.9%, 184F was 56.3% and 1246Y was 1.5%. The mutant allele 184F decreased from 73.7% in 2015 to 40.7% in 2017. The prevalence of haplotype NFD decreased from 71.4% in 2015 to 20.8% in 2017. Conclusions This study provides the first description of pfk13 and pfmdr1 genes variations in Bounkiling, a city in the Sédhiou Region of Senegal, contributing to closing the gap of information on anti-malaria drug resistance molecular markers in southern Senegal.

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