PMID- 30348661
OWN - NLM
STAT- MEDLINE
DCOM- 20200128
LR  - 20200309
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 63
IP  - 1
DP  - 2019 Jan
TI  - Promising New Antifungal Treatment Targeting Chorismate Synthase from 
      Paracoccidioides brasiliensis.
LID - 10.1128/AAC.01097-18 [doi]
LID - e01097-18
AB  - Paracoccidioidomycosis (PCM), caused by Paracoccidioides, is a systemic mycosis 
      with granulomatous character and a restricted therapeutic arsenal. The aim of 
      this work was to search for new alternatives to treat largely neglected tropical 
      mycosis, such as PCM. In this context, the enzymes of the shikimate pathway 
      constitute excellent drug targets for conferring selective toxicity because this 
      pathway is absent in humans but essential for the fungus. In this work, we have 
      used a homology model of the chorismate synthase (EC 4.2.3.5) from 
      Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual 
      screening and molecular dynamics testing to identify new potential inhibitors. 
      The best hit, CP1, successfully adhered to pharmacological criteria (adsorption, 
      distribution, metabolism, excretion, and toxicity) and was therefore used in in 
      vitro experiments. Here we demonstrate that CP1 binds with a dissociation 
      constant of 64 +/- 1 muM to recombinant chorismate synthase from P. brasiliensis and 
      inhibits enzymatic activity, with a 50% inhibitory concentration (IC(50)) of 
      47 +/- 5 muM. As expected, CP1 showed no toxicity in three cell lines. On the other 
      hand, CP1 reduced the fungal burden in lungs from treated mice, similar to 
      itraconazole. In addition, histopathological analysis showed that animals treated 
      with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large 
      areas with preserved architecture. Therefore, CP1 was able to control PCM in mice 
      with a lower inflammatory response and is thus a promising candidate and lead 
      structure for the development of drugs useful in PCM treatment.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Rodrigues-Vendramini, Franciele Abigail Vilugron
AU  - Rodrigues-Vendramini FAV
AD  - Department of Clinical Analysis and Biomedicine, Universidade Estadual de 
      Maringa, Maringa, Parana, Brazil.
FAU - Marschalk, Cidnei
AU  - Marschalk C
AD  - Department of Technology, Universidade Estadual de Maringa, Umuarama, Parana, 
      Brazil.
FAU - Toplak, Marina
AU  - Toplak M
AD  - Institute for Biochemistry, Graz University of Technology, Graz, Austria.
FAU - Macheroux, Peter
AU  - Macheroux P
AD  - Institute for Biochemistry, Graz University of Technology, Graz, Austria.
FAU - Bonfim-Mendonca, Patricia de Souza
AU  - Bonfim-Mendonca PS
AD  - Department of Clinical Analysis and Biomedicine, Universidade Estadual de 
      Maringa, Maringa, Parana, Brazil.
FAU - Svidzinski, Terezinha Inez Estivalet
AU  - Svidzinski TIE
AD  - Department of Clinical Analysis and Biomedicine, Universidade Estadual de 
      Maringa, Maringa, Parana, Brazil.
FAU - Seixas, Flavio Augusto Vicente
AU  - Seixas FAV
AD  - Department of Technology, Universidade Estadual de Maringa, Umuarama, Parana, 
      Brazil.
FAU - Kioshima, Erika Seki
AU  - Kioshima ES
AD  - Department of Clinical Analysis and Biomedicine, Universidade Estadual de 
      Maringa, Maringa, Parana, Brazil eskioshima@gmail.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181221
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (Antifungal Agents)
RN  - 0 (Quinolines)
RN  - 304NUG5GF4 (Itraconazole)
RN  - EC 4.2.3.5 (chorismate synthase)
RN  - EC 4.6.- (Phosphorus-Oxygen Lyases)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antifungal Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Drug Discovery/*methods
MH  - HeLa Cells
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Itraconazole/pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Microbial Sensitivity Tests
MH  - Microscopy, Electron, Scanning
MH  - Molecular Dynamics Simulation
MH  - Paracoccidioides/classification/*drug effects/isolation & purification
MH  - Paracoccidioidomycosis/*drug therapy
MH  - Phosphorus-Oxygen Lyases/*antagonists & inhibitors
MH  - Pulmonary Fibrosis/drug therapy/microbiology
MH  - Quinolines/*pharmacology
MH  - Sequence Analysis, Protein
PMC - PMC6325199
OTO - NOTNLM
OT  - chorismate synthase
OT  - molecular modeling
OT  - new antifungal
OT  - paracoccidioidomycosis
OT  - virtual screening
EDAT- 2018/10/24 06:00
MHDA- 2020/01/29 06:00
PMCR- 2019/06/21
CRDT- 2018/10/24 06:00
PHST- 2018/06/06 00:00 [received]
PHST- 2018/10/13 00:00 [accepted]
PHST- 2018/10/24 06:00 [pubmed]
PHST- 2020/01/29 06:00 [medline]
PHST- 2018/10/24 06:00 [entrez]
PHST- 2019/06/21 00:00 [pmc-release]
AID - AAC.01097-18 [pii]
AID - AAC01097-18 [pii]
AID - 10.1128/AAC.01097-18 [doi]
PST - epublish
SO  - Antimicrob Agents Chemother. 2018 Dec 21;63(1):e01097-18. doi: 
      10.1128/AAC.01097-18. Print 2019 Jan.