Faculty Opinions recommendation of Azole resistance of Aspergillus fumigatus biofilms is partly associated with efflux pump activity.

2011 ◽  
Author(s):  
S Arun Balajee ◽  
Eszter Deak
Keyword(s):  
Aspergillus Fumigatus ◽  
Efflux Pump ◽  
Azole Resistance ◽  
Pump Activity

scholarly journals Azole Resistance of Aspergillus fumigatus Biofilms Is Partly Associated with Efflux Pump Activity

2011 ◽  
Vol 55 (5) ◽  
pp. 2092-2097 ◽  
Author(s):  
Ranjith Rajendran ◽  
Eilidh Mowat ◽  
Elaine McCulloch ◽  
David F. Lappin ◽  
Brian Jones ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Azole Resistance ◽  
Dependent Manner ◽  
Content Type ◽  
Quantitative Expression ◽  
Pump Activity ◽  
Competitive Substrate

ABSTRACTThis study investigated the phase-dependent expression and activity of efflux pumps inAspergillus fumigatustreated with voriconazole. Fourteen strains were shown to become increasingly resistant in the 12-h (16- to 128-fold) and 24-h (>512-fold) phases compared to 8-h germlings. An Ala-Nap uptake assay demonstrated a significant increase in efflux pump activity in the 12-h and 24-h phases (P< 0.0001). The efflux pump activity of the 8-h germling cells was also significantly induced by voriconazole (P< 0.001) after 24 h of treatment. Inhibition of efflux pump activity with the competitive substrate MC-207,110 reduced the voriconazole MIC values for theA. fumigatusgermling cells by 2- to 8-fold. Quantitative expression analysis ofAfuMDR4mRNA transcripts showed a phase-dependent increase as the mycelial complexity increased, which was coincidental with a strain-dependent increase in azole resistance. Voriconazole also significantly induced this in a time-dependent manner (P< 0.001). Finally, anin vivomouse biofilm model was used to evaluate efflux pump expression, and it was shown thatAfuMDR4was constitutively expressed and significantly induced by treatment with voriconazole after 24 h (P< 0.01). Our results demonstrate that efflux pumps are expressed in complexA. fumigatusbiofilm populations and that this contributes to azole resistance. Moreover, voriconazole treatment induces efflux pump expression. Collectively, these data may provide evidence for azole treatment failures in clinical cases of aspergillosis.

Azole resistance inCandida albicansfrom animals: Highlights on efflux pump activity and gene overexpression

Mycoses ◽  
2017 ◽  
Vol 60 (7) ◽  
pp. 462-468 ◽  
Author(s):  
Marcos Fábio Gadelha Rocha ◽  
Silviane Praciano Bandeira ◽  
Lucas Pereira de Alencar ◽  
Luciana Magalhães Melo ◽  
Jamille Alencar Sales ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Gene Overexpression ◽  
Azole Resistance ◽  
Pump Activity

scholarly journals Aspergillus fumigatusAfssn3-Afssn8Pair Reverse Regulates Azole Resistance by Conferring Extracellular Polysaccharide, Sphingolipid Pathway Intermediates, and Efflux Pumps to Biofilm

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Nanbiao Long ◽  
Liping Zeng ◽  
Shanlei Qiao ◽  
Lei Li ◽  
Guowei Zhong
Keyword(s):  
Amino Acids ◽  
Aspergillus Fumigatus ◽  
Biofilm Formation ◽  
Efflux Pump ◽  
Extracellular Polysaccharide ◽  
Azole Resistance ◽  
Drug Penetration ◽  
Reverse Genetic ◽  
Content Type ◽  
Barrier Layers

ABSTRACTAntifungal treatment is often ineffectual, partly because of biofilm formation. In this study, by using a combined forward and reverse genetic strategy, we identified that nucleus-localized AfSsn3 and its partner AfSsn8, which constitute a Cdk8-cyclin pair, are required for azole resistance inAspergillus fumigatus. Deletion ofAfssn3led to increased absorption and utilization of glucose and amino acids. Interestingly, absorption and utilization of glucose accelerated the extracellular polysaccharide formation, while utilization of the amino acids serine, threonine, and glycine increased sphingolipid pathway intermediate accumulation. In addition, the absence ofAfssn3induced the activity of the efflux pump proteins. These factors indicate the mature biofilm is responsible for the major mechanisms ofA. fumigatusresistance to azoles in the ΔAfssn3mutant. Collectively, the loss ofAfssn3led to two “barrier” layers between the intracellular and extracellular spaces, which consequently decreased drug penetration into the cell.

scholarly journals The C2H2 Transcription Factor SltA Contributes to Azole Resistance by Coregulating the Expression of the Drug Target Erg11A and the Drug Efflux Pump Mdr1 in Aspergillus fumigatus

2021 ◽  
Author(s):  
Wenlong Du ◽  
Pengfei Zhai ◽  
Tingli Wang ◽  
Michael J Bromley ◽  
Yuanwei Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Fungal Pathogens ◽  
Efflux Pump ◽  
Antifungal Drugs ◽  
Ergosterol Biosynthesis ◽  
Azole Resistance ◽  
Drug Efflux ◽  
Mobility Shift ◽  
Drug Efflux Pump

The emergence of azole-resistant fungal pathogens has posed a great threat to public health worldwide. Although the molecular mechanism of azole resistance has been extensively investigated, the potential regulators of azole resistance remain largely unexplored. Here we identified a new function of the fungal specific C2H2 zinc finger transcription factor SltA (involved in salt-tolerance pathway) in the regulation of azole resistance of the human fungal pathogen Aspergillus fumigatus. Lack of SltA results in an itraconazole hypersusceptibility phenotype. Transcriptional profiling combined with LacZ reporter analysis and electrophoretic mobility shift assays (EMSA) demonstrate that SltA is involved in its own transcriptional regulation and also regulates the expression of genes related to ergosterol biosynthesis (erg11A, erg13A and erg24A) and drug efflux pumps (mdr1, mfsC and abcE) by directly binding to the conserved 5’-AGGCA-3’ motif in their promoter regions, and this binding is dependent on the conserved cysteine and histidine within the C2H2 DNA binding domain of SltA. Moreover, overexpression of erg11A or mdr1 rescues sltA deletion defects under itraconazole conditions, suggesting that erg11A and mdr1 are related to sltA-mediated itraconazole resistance. Most importantly, deletion of SltA in laboratory-derived and clinical azole-resistant isolates significantly attenuates drug resistance. Collectively, we have identified a new function of the transcription factor SltA in regulating azole resistance by coordinately mediating the key azole target Erg11A and the drug efflux pump Mdr1, and targeting SltA may provide a potential strategy for intervention of clinical azole-resistant isolates to improve the efficiency of currently approved antifungal drugs.

Overexpression of efflux pump genes is an alternative mechanism of voriconazole resistance in Aspergillus fumigatus

2019 ◽  
Vol 19 ◽  
Author(s):  
Maryam Moazeni ◽  
Narges Aslani ◽  
Mojtaba Nabili ◽  
Hamid Badali
Keyword(s):  
Aspergillus Fumigatus ◽  
Fungal Pathogens ◽  
Efflux Pump ◽  
Azole Resistance ◽  
Alternative Mechanism ◽  
Efflux Transporter ◽  
Environmental Isolates ◽  
Chain Reaction ◽  
Over Expression ◽  
Polymerase Chain

Background: The overexpression of the efflux transporter genes is one of the important mechanisms of resistance in fungal pathogens such as Candida and Aspergillus species. Objective: Here, the expression alterations of drug efflux transporter genes were evaluated in non-Cyp51A voriconazole-resistant Aspergillus fumigatus isolates. Methods: Six A. fumigatus isolates including four voriconazole-resistant isolates with and without azole-resistance-related mutations in addition to two susceptible A. fumigatus isolates were selected from 300 previously characterized A. fumigatus clinical and environmental isolates received during 2013-2015. In order to extract RNA, the minimum inhibitory concentrations (MICs) for the isolates were determined according to the broth microdilution protocol regarding the Clinical and Laboratory Standards Institute document M38-A2 (CLSI, 2008). Alteration in the expression of AfuMDR1, AfuMDR2, AfuMDR3, AfuMDR4, Cyp51A, and atrF was studied using the real-time polymerase chain reaction assay. Results: Based on REST® output, a significant overexpression of atrF, AfuMDR1, AfuMDR3, and AfuMDR4/Cyp51A, atrF, AfuMDR2, AfuMDR4 genes were observed in the isolates without azole-resistance-related mutations, respectively. No significant over expression was seen in the isolates with T34/L98H except for the AfuMDR3 and AfuMDR4(P<0.05). Conclusion: Our results support the hypothesis that efflux pump transporters can contribute to voriconazole resistance in A. fumigatus.

scholarly journals New Trimethoprim-Like Molecules: Bacteriological Evaluation and Insights into Their Action

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 709
Author(s):  
Marta Jorba ◽  
Marina Pedrola ◽  
Ouldouz Ghashghaei ◽  
Rocío Herráez ◽  
Lluis Campos-Vicens ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Efflux Pump ◽  
Synergistic Effects ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Detailed Characterization ◽  
Low Concentrations ◽  
Pump Activity ◽  
Bacteriological Evaluation ◽  
Kinetics Of

This work reports a detailed characterization of the antimicrobial profile of two trimethoprim-like molecules (compounds 1a and 1b) identified in previous studies. Both molecules displayed remarkable antimicrobial activity, particularly when combined with sulfamethoxazole. In disk diffusion assays on Petri dishes, compounds 1a and 1b showed synergistic effects with colistin. Specifically, in combinations with low concentrations of colistin, very large increases in the activities of compounds 1a and 1b were determined, as demonstrated by alterations in the kinetics of bacterial growth despite only slight changes in the fractional inhibitory concentration index. The effect of colistin may be to increase the rate of antibiotic entry while reducing efflux pump activity. Compounds 1a and 1b were susceptible to extrusion by efflux pumps, whereas the inhibitor phenylalanine arginyl β-naphthylamide (PAβN) exerted effects similar to those of colistin. The interactions between the target enzyme (dihydrofolate reductase), the coenzyme nicotinamide adenine dinucleotide phosphate (NADPH), and the studied molecules were explored using enzymology tools and computational chemistry. A model based on docking results is reported.

scholarly journals The TonB system in Aeromonas hydrophila NJ-35 is essential for MacA2B2 efflux pump-mediated macrolide resistance

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Yuhao Dong ◽  
Qing Li ◽  
Jinzhu Geng ◽  
Qing Cao ◽  
Dan Zhao ◽  
...  
Keyword(s):  
Aeromonas Hydrophila ◽  
Efflux Pump ◽  
Fold Increase ◽  
Activity Level ◽  
Macrolide Resistance ◽  
Wild Type ◽  
Iron Deprivation ◽  
Pump Activity ◽  
Tonb System ◽  
Increased Sensitivity

AbstractThe TonB system is generally considered as an energy transporting device for the absorption of nutrients. Our recent study showed that deletion of this system caused a significantly increased sensitivity of Aeromonas hydrophila to the macrolides erythromycin and roxithromycin, but had no effect on other classes of antibiotics. In this study, we found the sensitivity of ΔtonB123 to all macrolides tested revealed a 8- to 16-fold increase compared with the wild-type (WT) strain, but this increase was not related with iron deprivation caused by tonB123 deletion. Further study demonstrated that the deletion of tonB123 did not damage the integrity of the bacterial membrane but did hinder the function of macrolide efflux. Compared with the WT strain, deletion of macA2B2, one of two ATP-binding cassette (ABC) types of the macrolide efflux pump, enhanced the sensitivity to the same levels as those of ΔtonB123. Interestingly, the deletion of macA2B2 in the ΔtonB123 mutant did not cause further increase in sensitivity to macrolide resistance, indicating that the macrolide resistance afforded by the MacA2B2 pump was completely abrogated by tonB123 deletion. In addition, macA2B2 expression was not altered in the ΔtonB123 mutant, indicating that any influence of TonB on MacA2B2-mediated macrolide resistance was at the pump activity level. In conclusion, inactivation of the TonB system significantly compromises the resistance of A. hydrophila to macrolides, and the mechanism of action is related to the function of MacA2B2-mediated macrolide efflux.

Genetic Diversity and Azole Resistance Among Natural Aspergillus fumigatus Populations in Yunnan, China

2021 ◽  
Author(s):  
Duanyong Zhou ◽  
Ruirui Wang ◽  
Xiao Li ◽  
Bin Peng ◽  
Guangzhu Yang ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Aspergillus Fumigatus ◽  
Azole Resistance
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