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PubMed2005

Analysis of Salmonella enterica serotype Typhi pulsed-field gel electrophoresis patterns associated with international travel.

Typhoid fever is a significant cause of morbidity and mortality worldwide, causing an estimated 16 million cases and 600,000 deaths annually. Although overall rates of the disease have dramatically decreased in the United States, the number of travel-related infections has increased in recent decades. Drug resistance among Salmonella enterica serotype Typhi strains has emerged worldwide, making antimicrobial susceptibility testing an important function in public health laboratories. Pulsed-field gel electrophoresis (PFGE) subtyping of food-borne and waterborne pathogens has proven to be a valuable tool for the detection of outbreaks and laboratory-based surveillance. This retrospective study examined the distribution of PFGE patterns of S. enterica serotype Typhi isolates from patients with a history of international travel. Isolates were collected as part of a passive laboratory-based antimicrobial susceptibility surveillance study. Isolates were PFGE subtyped by using the restriction enzyme XbaI to restrict the total genomic DNA. Isolates indistinguishable with XbaI were further characterized using the restriction enzyme BlnI. A total of 139 isolates were typed, representing travel to 31 countries. Restriction fragment patterns consisted of 14 to 18 fragments ranging in size from 580 to 40 kbp. Seventy-nine unique PFGE patterns were generated using XbaI. Isolates from the same geographic region did not necessarily have similar PFGE patterns. Of the 139 isolates, 46 (33%) were resistant to more than one antimicrobial agent (multidrug resistant [MDR]). Twenty-seven (59%) of 46 MDR isolates had indistinguishable PFGE patterns with both XbaI and BlnI. It appears that MDR S. enterica serotype Typhi has emerged as a predominant clone in Southeast Asia and the Indian subcontinent.

Drug Resistance, Multiple, Bacterial↗

PubMed2006

Drug resistance in Mycobacterium tuberculosis.

Anti-tuberculosis drugs are a two-edged sword. While they destroy pathogenic M. tuberculosis they also select for drug resistant bacteria against which those drugs are then ineffective. Global surveillance has shown that drug resistant Tuberculosis is widespread and is now a threat to tuberculosis control programs in many countries. Application of molecular methods during the last decade has greatly changed our understanding of drug resistance in tuberculosis. Application of molecular epidemiological methods was also central to the description of outbreaks of drug resistance in Tuberculosis. This review describes recommendations for Tuberculosis treatment according to the WHO guidelines, the drug resistance problem in the world, mechanisms of resistance to first line and second line drugs and applications of molecular methods to detect resistance causing gene mutations. It is envisaged that molecular techniques may be important adjuncts to traditional culture based procedures to rapidly screen for drug resistance. Prospective analysis and intervention to prevent transmission may be particularly helpful in areas with ongoing transmission of drug resistant strains as recent mathematical modeling indicate that the burden of MDR-TB cannot be contained in the absence of specific efforts to limit transmission.

Antitubercular Agents↗

PubMed2005

A new function of isonitrile as an inhibitor of the Pdr5p multidrug ABC transporter in Saccharomyces cerevisiae.

Pdr5p in Saccharomyces cerevisiae is a functional homologue of mammalian P-glycoprotein implicated in multidrug resistance (MDR). In order to obtain useful inhibitors to overcome MDR in clinical tumors, screening of Pdr5p inhibitors has been carried out. We isolated a fungal strain producing Pdr5p inhibitors using our original assay system, and it was classified as Trichoderma sp. P24-3. The purified inhibitor was identified as isonitrile, 3-(3'-isocyano-cyclopent-2'-enylidene)-propionic acid, a compound whose carboxyl residue is essential for the inhibitory activity. A non-toxic concentration of the isonitrile (41.5 microg/ml, 255 microM) inhibited Pdr5p-mediated efflux of cycloheximide or cerulenin in Pdr5p-overexpressing cells. In addition, addition of the isonitrile led to accumulation of rhodamine 6G, a substrate of Pdr5p, in the Pdr5p-overexpressing cells. The inhibitory profiles of the isonitrile against S1360 mutants (S1360A and S1360F) of Pdr5p were different from those of FK506 and enniatin. The isonitrile did not influence PDR5 gene expression and the amount of Pdr5 protein, nor did it inhibit the function of Snq2p, a homologue of Pdr5p. Interestingly, the isonitrile inhibited the function of Cdr1p and Cdr2p, Pdr5p homologues in pathogenic yeast Candida albicans. Thus, it was found that the isonitrile shows a different inhibitory spectrum from that of FK506 and enniatin as a potent inhibitor for Pdr5p, Cdr1p, and Cdr2p.

ATP-Binding Cassette Transporters↗

PubMed2006

Genes that enhance the ecological fitness of Shewanella oneidensis MR-1 in sediments reveal the value of antibiotic resistance.

Environmental bacteria persist in various habitats, yet little is known about the genes that contribute to growth and survival in their respective ecological niches. Signature-tagged mutagenesis (STM) of Shewanella oneidensis MR-1 coupled with a screen involving incubations of mutant strains in anoxic aquifer sediments allowed us to identify 47 genes that enhance fitness in sediments. Gene functions inferred from annotations provide us with insight into physiological and ecological processes that environmental bacteria use while growing in sediment ecosystems. Identification of the mexF gene and other potential membrane efflux components by STM demonstrated that homologues of multidrug resistance genes present in pathogens are required for sediment fitness of nonpathogenic bacteria. Further studies with a mexF deletion mutant demonstrated that the multidrug resistance pump encoded by mexF is required for resistance to antibiotics, including chloramphenicol and tetracycline. Chloramphenicol-adapted cultures exhibited mutations in the gene encoding a TetR family regulatory protein, indicating a role for this protein in regulating expression of the mexEF operon. The relative importance of mexF for sediment fitness suggests that antibiotic efflux may be a required process for bacteria living in sediment systems.

Anti-Bacterial Agents↗

PubMed2006

A multidrug resistance transporter in Magnaporthe is required for host penetration and for survival during oxidative stress.

In prokaryotes and eukaryotes, multidrug resistance (MDR) transporters use energy-dependent efflux action to regulate the intracellular levels of antibiotic or xenobiotic compounds. Using mutational analysis of ABC3, we define an important role for such MDR-based efflux during the host penetration step of Magnaporthe grisea pathogenesis. Mutants lacking ABC3 were completely nonpathogenic but were surprisingly capable of penetrating thin cellophane membranes to some extent. The inability of abc3Delta to penetrate the host surface was most likely a consequence of excessive buildup of peroxide and accumulation of an inhibitory metabolite(s) within the mutant appressoria. Treatment with antioxidants partially suppressed the host penetration defects in the abc3Delta mutant. abc3Delta was highly sensitive to oxidative stress and was unable to survive the host environment and invasive growth conditions. ABC3 transcript levels were redox-regulated, and on host surfaces, the activation of ABC3 occurred during initial stages of blast disease establishment. An Abc3-green fluorescent protein fusion localized to the plasma membrane in early appressoria (and in penetration hyphae) but became predominantly vacuolar during appressorial maturity. We propose that ABC3 function helps Magnaporthe to cope with cytotoxicity and oxidative stress within the appressoria during early stages of infection-related morphogenesis and likely imparts defense against certain antagonistic and xenobiotic conditions encountered during pathogenic development.

Drug Resistance, Multiple, Fungal↗

PubMed1999

Molecular characterization of an antibiotic resistance gene cluster of Salmonella typhimurium DT104.

Salmonella typhimurium phage type DT104 has become an important emerging pathogen. Isolates of this phage type often possess resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline (ACSSuT resistance). The mechanism by which DT104 has accumulated resistance genes is of interest, since these genes interfere with treatment of DT104 infections and might be horizontally transferred to other bacteria, even to unrelated organisms. Previously, several laboratories have shown that the antibiotic resistance genes of DT104 are chromosomally encoded and involve integrons. The antibiotic resistance genes conferring the ACSSuT-resistant phenotype have been cloned and sequenced. These genes are grouped within two district integrons and intervening plasmid-derived sequences. This sequence is potentially useful for detection of multiresistant DT104.

Amino Acid Sequence↗

PubMed2006

Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis.

The MDR1 gene is an attractive candidate gene for the pathogenesis of inflammatory bowel disease (IBD) and perhaps response to therapy, with evidences at both functional and genetic levels. Its product, the P-glycoprotein (P-gp) functions as a transmembrane efflux pump thus influencing disposition and response of many drugs, some of whom (i.e. glucocorticoids) central to IBD therapy. In addition P-gp is highly expressed in many epithelial surfaces, included gastrointestinal tract (G-I) with a putative role in decreasing the absorption of endogenous or exogenous toxins, and perhaps host-bacteria interaction. Many genetic variations of MDR1 gene has been described and in some instances evidences for different P-gp expression as well drugs metabolism have been provided. However data are often conflicting due to genetic heterogeneity and different methodologies employed. Perhaps the greatest piece of evidence of the physiological importance of P-gp in the G-I tract has come from the description of the mdr1 knock-out mice model, which develops a spontaneous colitis in a specific pathogen-free environment. Studies investigating MDR1 gene polymorphism and predisposition to IBD have also shown conflicting results, owing to the known difficulties in complex diseases, especially when the supposed genetic contribution is weak. In this study we have undertaken a meta-analysis of the available findings obtained with two SNPs polymorphism (C3435T and G2677T/A) in IBD; a significant association of 3435T allele and 3435TT genotype has been found with UC (OR = 1.17, P = 0.003 and OR = 1.36, P = 0.017, respectively). In contrast no association with CD and the G2677T/A polymorphism could be demonstrated.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Effect of drug resistance on the generation of secondary cases of tuberculosis.

BACKGROUND: The results of animal studies suggest that isoniazid-resistant strains of Mycobacterium tuberculosis are less pathogenic than isoniazid-susceptible strains. Here, we assess the relative pathogenicity of drug-resistant and drug-susceptible strains, in a human population. METHODS: We linked IS6110 genotype patterns of M. tuberculosis strains with drug-susceptibility test results and epidemiologic information for 85% of culture-positive incident cases of tuberculosis (TB) in San Francisco during 1991-1999. We assumed that drug-susceptible and drug-resistant strains were transmitted to secondary case patients if the drug-resistance and genotype patterns were identical. We calculated the number of secondary cases for each drug-resistance pattern and determined the relative secondary-case rate ratio (SR) of drug-resistant TB to drug-susceptible TB. RESULTS: There were 1800 patients with culture-positive TB, drug-susceptibility test results, and genotyping results. The overall SR of drug-resistant to drug-susceptible TB cases was 0.51 (95% confidence interval [CI], 0.37-0.69). The SR was 0.29 (95% CI, 0.15-0.57) for isoniazid-resistant strains, 0.10 (95% CI, 0.02-0.42) for strains resistant to both isoniazid and streptomycin, and 0.88 (95% CI, 0.53-1.47) for streptomycin-resistant strains. There were no secondary cases caused by multidrug-resistant (MDR) TB. The SR for rifampin-resistant cases was 2.33 (95% CI, 1.04-5.25). Seventy-eight percent (7/9) of the patients with rifampin-resistant secondary cases of TB were seropositive for human immunodeficiency virus. CONCLUSION: In the context of an effective TB program in San Francisco, strains that were resistant to isoniazid either alone or in combination with other drugs were less likely to result in secondary cases than were drug-susceptible strains. In this setting, isoniazid-resistant and MDR TB cases were not likely to produce new, incident drug-resistant TB cases.

Anti-Bacterial Agents↗

PubMed2004

SUMO modification of Huntingtin and Huntington's disease pathology.

Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.

Animals↗

PubMed2005

Nosocomial outbreak caused by multidrug-resistant Pseudomonas aeruginosa producing IMP-13 metallo-beta-lactamase.

An outbreak of Pseudomonas aeruginosa showing a multidrug-resistant (MDR) phenotype (including carbapenems, ceftazidime, cefepime, gentamicin, tobramycin, and fluoroquinolones) was observed, during a 5-month period, in a general intensive care unit of a large tertiary care and clinical research hospital in southern Italy. The outbreak involved 15 patients, with a total of 87 isolates, mostly from lower respiratory tract specimens. Analysis of isolates involved in the outbreak revealed production of metallo-beta-lactamase (MBL) activity, and genotyping by pulsed-field gel electrophoresis of genomic DNA digested by SpeI revealed clonal relatedness among isolates. Molecular analysis of the MBL determinant showed the presence of a bla(IMP-13) gene carried on a gene cassette inserted in a class 1 integron which also contained an aacA4 aminoglycoside resistance cassette encoding an AAC(6')-Ib enzyme. The bla(IMP-13)-containing integron and its genetic environment appeared to be similar to those found in P. aeruginosa isolates producing IMP-13 from a hospital in Rome. The bla(IMP-13) gene was not transferable by conjugation and was apparently carried on the chromosome. The outbreak was coincidental with a shortage of nursing personnel, and resolution was apparently associated with reinstatement of nursing personnel and reinforcement of general infection control practices within the intensive care unit. To our best knowledge this is the first description of a nosocomial outbreak of relatively large size caused by an IMP-producing gram-negative pathogen in Europe.

Cross Infection↗

PubMed2002

Transcription initiation of genes associated with azole resistance in Candida albicans.

Oral infections with the opportunistic pathogenic yeast Candida albicans are one of the earliest and most frequent infections in immunosuppressed individuals. In these populations, drug-resistant isolates have emerged with the widespread use of antifungal azole drugs. Many molecular mechanisms of resistance have been identified, including overexpression of two types of efflux pumps, the major facilitator MDR1 and the ABC-transporters (CDR1 and CDR2), and the overexpression or mutation of the target enzyme, ERG11. With overexpression of these four genes implicated in multidrug resistance, identification of regulatory regions of the promoters is important. 5' rapid amplification of cDNA ends (RACE) was used to identify transcription initiation sites for genes associated with multidrug resistance (CDR1, CDR2, MDR1 and ERG11). These results were confirmed by cloning and sequencing of 5' RACE products and by primer extension. This research will allow further analysis of the regulation of transcription for these genes.

ATP-Binding Cassette Transporters↗

PubMed2003

The role of multidrug efflux pumps in the antibiotic resistance of Pseudomonas aeruginosa and other gram-negative bacteria. Insights from the Society of Infectious Diseases Pharmacists.

Gram-negative bacteria remain clinically important pathogens in both hospital and community settings. Recent research indicates that efflux pumps play a prominent role in the multidrug resistance of Pseudomonas aeruginosa and many other gram-negative bacteria. Four multidrug efflux pump systems have been well characterized in P. aeruginosa: MexA-MexB-OprM, MexC-MexD-OprJ, MexE-MexF-OprN, and MexX-MexY-OprM. These efflux pumps have different substrate specificities, and their production and activity can be increased by many factors commonly present in infections (e.g., high inocula of bacteria, low pH, and stationary-phase growth). Moreover, fluoroquinolone antibiotics can commonly select mutants that constitutively overproduce Mex-Opr efflux pump systems. Based on most recent studies, the prevalence of efflux pump overproduction in clinical strains of P. aeruginosa may range from 14-75%. The best treatment for infections caused by bacteria that overproduce efflux pumps is unknown, but pharmacodynamic optimization of antibiotics and the use of antibiotic combinations that are substrates for different pump systems may represent reasonable strategies until more data are available.

Anti-Bacterial Agents↗

PubMed2005

Multidrug resistance in parasites: ABC transporters, P-glycoproteins and molecular modelling.

Parasitic diseases, caused by protozoa, helminths and arthropods, rank among the most important problems in human and veterinary medicine, and in agriculture, leading to debilitating sicknesses and loss of life. In the absence of vaccines and with the general failure of vector eradication programs, drugs are the main line of defence, but the newest drugs are being tracked by the emergence of resistance in parasites, sharing ominous parallels with multidrug resistance in bacterial pathogens. Any of a number of mechanisms will elicit a drug resistance phenotype in parasites, including: active efflux, reduced uptake, target modification, drug modification, drug sequestration, by-pass shunting, or substrate competition. The role of ABC transporters in parasitic multidrug resistance mechanisms is being subjected to more scrutiny, due in part to the established roles of certain ABC transporters in human diseases, and also to an increasing portfolio of ABC transporters from parasite genome sequencing projects. For example, over 100 ABC transporters have been identified in the Escherichia coli genome, but to date only about 65 in all parasitic genomes. Long established laboratory investigations are now being assisted by molecular biology, bioinformatics, and computational modelling, and it is in these areas that the role of ABC transporters in parasitic multidrug resistance mechanisms may be defined and put in perspective with that of other proteins. We discuss ABC transporters in parasites, and conclude with an example of molecular modelling that identifies a new interaction between the structural domains of a parasite P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Population genomics of drug resistance in Candida albicans.

We followed adaptation in experimental microbial populations to inhibitory concentrations of an antimicrobial drug. The evolution of drug resistance was accompanied in all cases by changes in gene expression that persisted in the absence of the drug; the new patterns of gene expression were constitutive. The changes in gene expression occurred in four replicate populations of the pathogenic fungus Candida albicans during 330 generations of evolution in the presence of the antifungal drug fluconazole. Genome-wide expression profiling of over 5,000 ORFs identified 301 whose expression was significantly modulated. Cluster analysis identified three distinct patterns of gene expression underlying adaptation to the drug. One pattern was unique to one population and included up-regulation of the multidrug ATP-binding cassette transporter gene, CDR2. A second pattern occurred at a late stage of adaptation in three populations; for two of these populations profiled earlier in their evolution, a different pattern was observed at an early stage of adaptation. The succession of early- and late-stage patterns of gene expression, both of which include up-regulation of the multidrug major facilitator transporter gene, MDR1, must represent a common program of adaptation to this antifungal drug. The three patterns of gene expression were also identified in fluconazole-resistant clinical isolates, providing further evidence that these patterns represent common programs of adaptation to fluconazole.

ATP-Binding Cassette Transporters↗

PubMed2006

Overexpression of the MDR1 gene is sufficient to confer increased resistance to toxic compounds in Candida albicans.

Overexpression of MDR1, which encodes a membrane transport protein of the major facilitator superfamily, is one mechanism by which the human fungal pathogen Candida albicans can develop increased resistance to the antifungal drug fluconazole and other toxic compounds. In clinical C. albicans isolates, constitutive MDR1 overexpression is accompanied by the upregulation of other genes, but it is not known if these additional alterations are required for Mdr1p function and drug resistance. To investigate whether MDR1 overexpression is sufficient to confer a drug-resistant phenotype in C. albicans, we expressed the MDR1 gene from the strong ADH1 promoter in C. albicans laboratory strains that did not express the endogenous MDR1 gene as well as in a fluconazole-resistant clinical C. albicans isolate in which the endogenous MDR1 alleles had been deleted and in a matched fluconazole-susceptible isolate from the same patient. Forced MDR1 overexpression resulted in increased resistance to the putative Mdr1p substrates cerulenin and brefeldin A, and this resistance did not depend on the additional alterations which occurred during drug resistance development in the clinical isolates. In contrast, artificial expression of the MDR1 gene from the ADH1 promoter did not enhance or only slightly enhanced fluconazole resistance, presumably because Mdr1p expression levels in the transformants were considerably lower than those observed in the fluconazole-resistant clinical isolate. These results demonstrate that MDR1 overexpression in C. albicans is sufficient to confer resistance to some toxic compounds that are substrates of this efflux pump but that the degree of resistance depends on the Mdr1p expression level.

Candida albicans↗

PubMed2002

The genetic basis of fluconazole resistance development in Candida albicans.

Infections by the opportunistic fungal pathogen Candida albicans are widely treated with the antifungal agent fluconazole that inhibits the biosynthesis of ergosterol, the major sterol in the fungal plasma membrane. The emergence of fluconazole-resistant C. albicans strains is a significant problem after long-term treatment of recurrent oropharyngeal candidiasis (OPC) in acquired immunodeficiency syndrome (AIDS) patients. Resistance can be caused by alterations in sterol biosynthesis, by mutations in the drug target enzyme, sterol 14alpha-demethylase (14DM), which lower its affinity for fluconazole, by increased expression of the ERG11 gene encoding 14DM, or by overexpression of genes coding for membrane transport proteins of the ABC transporter (CDR1/CDR2) or the major facilitator (MDR1) superfamilies. Different mechanisms are frequently combined to result in a stepwise development of fluconazole resistance over time. The MDR1 gene is not or barely transcribed during growth in vitro in fluconazole-susceptible C. albicans strains, but overexpressed in many fluconazole-resistant clinical isolates, resulting in reduced intracellular fluconazole accumulation. The activation of the gene in resistant isolates is caused by mutations in as yet unknown trans-regulatory factors, and the resulting constitutive high level of MDR1 expression causes resistance to other toxic compounds in addition to fluconazole. Disruption of both alleles of the MDR1 gene in resistant C. albicans isolates abolishes their resistance to these drugs, providing genetic evidence that MDR1 mediates multidrug resistance in C. albicans.

AIDS-Related Opportunistic Infections↗

PubMed2005

Mechanisms of azole resistance in a clinical isolate of Candida tropicalis.

Azole resistance has been insufficiently investigated in the yeast Candida tropicalis. Here we determined the molecular mechanisms responsible for azole resistance in a clinical isolate of this pathogenic yeast. Antifungal susceptibility testing performed by a disk diffusion method showed resistance or markedly decreased susceptibility to azoles, which was confirmed by determination of MICs. Considering the relationship between azole susceptibility and the respiration reported for other yeast species, the respiratory activity of this isolate was investigated. Flow cytometry using rhodamine 123 and oxygraphy demonstrated an increased respiratory activity, which was not linked to an overexpression or increased number of copies of the mitochondrial genome. Among previously described resistance mechanisms, an increased activity of efflux pumps was investigated by flow cytometry using rhodamine 6G. However, the efflux of rhodamine 6G was lower in the resistant isolate than in susceptible ones. Likewise, real-time reverse transcription-PCR quantification of the expression of C. tropicalis MDR1 (CtMDR1), which encodes an efflux protein belonging to the major facilitator superfamily, did not show overexpression of this gene. In contrast, the resistant isolate overexpressed the CtERG11 gene coding for lanosterol 14alpha-demethylase. This was in agreement with the larger amount of ergosterol found in this isolate. Moreover, sequencing of CtERG11 showed a point mutation leading to a tyrosine substitution in the protein sequence, which might lead to decreased binding affinity for azoles. In conclusion, overexpression of CtERG11 associated with a missense mutation in this gene seemed to be responsible for the acquired azole resistance of this clinical isolate.

Azoles↗

PubMed2003

Genome-wide expression profile analysis reveals coordinately regulated genes associated with stepwise acquisition of azole resistance in Candida albicans clinical isolates.

Candida albicans is an opportunistic human fungal pathogen and a causative agent of oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among patients with AIDS. Fluconazole and other azole antifungal agents have proven effective in the management of OPC; however, with increased use of these agents treatment failures have occurred. Such failures have been associated with the emergence of azole-resistant strains of C. albicans. In the present study we examined changes in the genome-wide gene expression profile of a series of C. albicans clinical isolates representing the stepwise acquisition of azole resistance. In addition to genes previously associated with azole resistance, we identified many genes whose differential expression was for the first time associated with this phenotype. Furthermore, the expression of these genes was correlated with that of the known resistance genes CDR1, CDR2, and CaMDR1. Genes coordinately regulated with the up-regulation of CDR1 and CDR2 included the up-regulation of GPX1 and RTA3 and the down-regulation of EBP1. Genes coordinately regulated with the up-regulation of CaMDR1 included the up-regulation of IFD1, IFD4, IFD5, IFD7, GRP2, DPP1, CRD2, and INO1 and the down-regulation of FET34, OPI3, and IPF1222. Several of these appeared to be coordinately regulated with both the CDR genes and CaMDR1. Many of these genes are involved in the oxidative stress response, suggesting that reduced susceptibility to oxidative damage may contribute to azole resistance. Further evaluation of the role these genes and their respective gene products play in azole antifungal resistance is warranted.

Antifungal Agents↗