PMID- 25850856
OWN - NLM
STAT- MEDLINE
DCOM- 20160314
LR  - 20161125
IS  - 1460-2709 (Electronic)
IS  - 1369-3786 (Linking)
VI  - 53
IP  - 5
DP  - 2015 Jun
TI  - Transcriptional profile of the human pathogenic fungus Paracoccidioides lutzii in 
      response to sulfamethoxazole.
PG  - 477-92
LID - 10.1093/mmy/myv011 [doi]
AB  - Paracoccidioidomycosis (PCM) is the most prevalent mycosis in Latin America and 
      is caused by a group of fungi within the Paracoccidioides genus. The disease may 
      present clinical and pathological manifestations ranging from asymptomatic 
      pneumonia pulmonary lesions, to disseminated forms involving multiple organs. 
      Sulfonamides were the first drugs used to treat PCM and are still used against 
      this fungal infection. Sulfa drugs are competitive antagonists of rho-aminobenzoic 
      acid (PABA), a reaction catalyzed by dihydropteroate synthase (DHPS). However, 
      the molecular effects of sulfonamides against the Paracoccidioides genus are 
      unknown. The aim of this work was to investigate the global mechanism of action 
      of sulfamethoxazole on Paracoccidioides lutzii. Yeast cells were grown on minimum 
      medium in the presence or absence of sulfamethoxazole to construct EST libraries. 
      The representational difference analysis (RDA) technique was used to identify up- 
      and down-regulated P. lutzii genes after treatment with sulfamethoxazole. 
      Approximately six transcripts related to mitochondrial function were 
      differentially expressed. To confirm the RDA and bioinformatics results, several 
      relevant genes were studied with quantitative real-time polymerase chain reaction 
      (qRT-PCR) to evaluate their levels of expression. To confirm the impact of 
      sulfamethoxazole on mitochondria, we measured the reduction of tetrazolium salt 
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) by P. lutzii 
      with or without exposure to the drug. MTT assays reveal that sulfamethoxazole 
      produces a marked dose-dependent adverse effect on P. lutzii. The transcriptional 
      activity of selected genes in infected macrophages corroborated our in vitro 
      results. The results indicated that sulfamethoxazole acts in P. lutzii as a 
      competitor for amino acid, nucleic acids and folate cofactor biosynthesis, 
      disrupting mitochondrial functions.
CI  - (c) The Author 2015. Published by Oxford University Press on behalf of The 
      International Society for Human and Animal Mycology. All rights reserved. For 
      permissions, please e-mail: journals.permissions@oup.com.
FAU - Zambuzzi-Carvalho, Patricia Fernanda
AU  - Zambuzzi-Carvalho PF
AD  - Laboratorio de Biologia Molecular, Instituto de Ciencias Biologicas, Universidade 
      Federal de Goias, Goiania, GO, Brazil.
FAU - Fernandes, Amanda Gregorim
AU  - Fernandes AG
AD  - Laboratorio de Biologia Molecular, Instituto de Ciencias Biologicas, Universidade 
      Federal de Goias, Goiania, GO, Brazil.
FAU - Valadares, Marize Campos
AU  - Valadares MC
AD  - Laboratorio de Farmacologia e Toxicologia Celular, Faculdade de Farmacia, 
      Universidade Federal de Goias, Goiania, GO, Brazil.
FAU - Tavares, Patricia de Mello
AU  - Tavares Pde M
AD  - Departments of Medicine and Microbiology and Immunology, Albert Einstein College 
      of Medicine, New York, NY, USA.
FAU - Nosanchuk, Joshua D
AU  - Nosanchuk JD
AD  - Departments of Medicine and Microbiology and Immunology, Albert Einstein College 
      of Medicine, New York, NY, USA.
FAU - Soares, Celia Maria de Almeida
AU  - Soares CM
AD  - Laboratorio de Biologia Molecular, Instituto de Ciencias Biologicas, Universidade 
      Federal de Goias, Goiania, GO, Brazil.
FAU - Pereira, Maristela
AU  - Pereira M
AD  - Laboratorio de Biologia Molecular, Instituto de Ciencias Biologicas, Universidade 
      Federal de Goias, Goiania, GO, Brazil maristelaufg@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150407
PL  - England
TA  - Med Mycol
JT  - Medical mycology
JID - 9815835
RN  - 0 (Anti-Infective Agents)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - EUY85H477I (thiazolyl blue)
RN  - JE42381TNV (Sulfamethoxazole)
SB  - IM
MH  - Anti-Infective Agents/*metabolism
MH  - Expressed Sequence Tags
MH  - *Gene Expression Profiling
MH  - Gene Expression Regulation, Fungal/*drug effects
MH  - Metabolic Networks and Pathways/drug effects
MH  - Microbial Viability/drug effects
MH  - Mitochondria/drug effects
MH  - Oxidation-Reduction
MH  - Paracoccidioides/*drug effects
MH  - Real-Time Polymerase Chain Reaction
MH  - Sulfamethoxazole/*metabolism
MH  - Tetrazolium Salts/metabolism
MH  - Thiazoles/metabolism
OTO - NOTNLM
OT  - Paracoccidioides lutzii
OT  - antifungal
OT  - representational difference analysis
OT  - sulfamethoxazole
OT  - transcriptome
EDAT- 2015/04/09 06:00
MHDA- 2016/03/15 06:00
CRDT- 2015/04/09 06:00
PHST- 2015/01/27 00:00 [accepted]
PHST- 2014/10/15 00:00 [received]
PHST- 2015/04/09 06:00 [entrez]
PHST- 2015/04/09 06:00 [pubmed]
PHST- 2016/03/15 06:00 [medline]
AID - myv011 [pii]
AID - 10.1093/mmy/myv011 [doi]
PST - ppublish
SO  - Med Mycol. 2015 Jun;53(5):477-92. doi: 10.1093/mmy/myv011. Epub 2015 Apr 7.