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Last update 08 May 2025

SMDT1

Last update 08 May 2025

Basic Info

Synonyms

C22orf32, DDDD, dJ186O1.1

+ [5]

Introduction

Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988, PubMed:30454562, PubMed:31080062, PubMed:32315830, PubMed:32494073, PubMed:32762847, PubMed:32790952, PubMed:33296646). Required to bridge the calcium-sensing proteins MICU1 with the calcium-conducting subunit MCU (PubMed:24231807, PubMed:30454562, PubMed:32494073, PubMed:32762847, PubMed:32790952). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988, PubMed:31080062, PubMed:32315830, PubMed:33296646).

Drugs associated with SMDT1

NAV-205

Target

SMDT1

Mechanism

SMDT1 inhibitors

Active Org.

Navrogen, Inc.

Originator Org.

Navrogen, Inc.

Active Indication

Solid tumor

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with SMDT1

100 Translational Medicine associated with SMDT1

0 Patents (Medical) associated with SMDT1

335

Literatures (Medical) associated with SMDT1

03 May 2025·Journal of Biomolecular Structure and Dynamics

Comprehending conformational changes in EmrE, multidrug transporter at different pH: insights from molecular dynamics simulations

Article

Author: Kaur, Manpreet ; Arya, Preeti ; Singh, Balvinder ; Chosyang, Stanzin

EmrE is a small multidrug resistance (SMR) pump of antiparallel topology that confers resistance to a broad range of polyaromatic cations in Escherichia coli. Atomic-level understanding of conformational changes for the selectivity of substrate and transport of a diverse array of drugs through the smallest known efflux pumps is crucial to multi-drug resistance. Therefore, the present study aims to provide insights into conformational changes during the transport through EmrE transporter at different pH. Molecular dynamics simulations have been carried out on the complete structure of EmrE in the absence of substrate. Computational analyses such as secondary structure, principal component, dynamic cross-correlation matrix, and hydrogen bond calculations have been performed. Analysis of MD trajectories in this study revealed pH-dependent interactions that influenced the structural dynamics of EmrE. Notably, at high pH, Glu14 and Tyr60 in both monomers formed electrostatic interactions, while these interactions decreased significantly at a low pH. Interestingly, a kink at helix 3 (H3) and dual open conformation of EmrE at low pH were also observed in contrast to a closed state discerned towards the periplasmic side at high pH. Significant interactions between C-terminal residues and residues at the edge of H1 & Loop1 and H3 & Loop3 were identified, suggesting their role in stabilizing the closed conformation of EmrE at the periplasmic end under high pH conditions. The present study enhances our understanding of EmrE's conformational changes, shedding light on the pH-dependent mechanisms that are likely to impact its function in multi-drug resistance.

01 May 2025·Journal of Global Antimicrobial Resistance

Genetic determinants and phenotypic characteristics of heavy metal and biocide tolerance among multidrug-resistant and susceptible Gram-negative bacilli clinical isolates

Article

Author: Ferreira, Joseane Cristina ; Abichabki, Nathália ; Martinez, Roberto ; Andrade, Leonardo Neves ; Darini, Ana Lucia da Costa ; Moreira, Natália Columbaro

Antimicrobial resistance is a major health care problem as well as a concern for global public health. As a result, the use of nonantibiotic antimicrobials, such as heavy metals and biocides, has increased in a bid to control the spread of antibiotic-resistant bacteria. Consequently, heavy metal tolerance genes (HMTGs) and biocide tolerance genes (BTGs) have been more frequently detected in Gram-negative bacilli. In this study, we searched for acquired HMTGs, BTGs, and antibiotic resistance genes (ARGs) and determined the MICs of common heavy metals and biocides in multidrug-resistant and susceptible Gram-negative bacilli clinical isolates. A high frequency of silA and pcoD genes was mainly detected among Klebsiella spp. and Enterobacter cloacae regardless of their susceptible profile. The merA gene was also found in isolates carrying silA/pcoD genes. ARGs were detected in isolates that harboured silA and/or pcoD genes. BTGs (qacΔE, ydgE, ydgF, mdfA, and emrE) were mostly detected in Klebsiella pneumoniae and E. cloacae isolates regardless of their susceptibility profile, and these isolates often co-harboured HMTGs and/or ARGs. Higher copper sulphate MIC values were obtained under aerobic conditions, regardless of the presence or absence of pcoD and/or silA genes. Nevertheless, in most isolates carrying pcoD/silA, higher copper sulphate MIC values were determined under anaerobic conditions. Regarding AgNO₃, no significant differences in MIC values were observed for isolates with or without the silA gene. Our results show a broad distribution of HMTGs, BTGs, and ARGs in bacteria causing health care-associated infections, which could contribute to the co-selection of hospital pathogens resistant to multiple and diverse antimicrobials.

23 Apr 2025·Applied and Environmental Microbiology

Large-scale phenotypic and genomic analysis of Listeria monocytogenes reveals diversity in the sensitivity to quaternary ammonium compounds but not to peracetic acid

Article

Author: Karpíšková, Renáta ; Leekitcharoenphon, Pimlapas ; Pietzka, Ariane ; Tosun, Elif Seyda ; Okholm, Anders Hauge ; De Angelis, Maria Elisabetta ; Gomez, Diego ; Heir, Even ; Gmeiner, Alexander ; Centorame, Patrizia ; Rychli, Kathrin ; Ivanova, Mirena ; Møretrø, Trond ; Zdovc, Irena ; Papić, Bojan ; Truelstrup Hansen, Lisbeth ; Etter, Andrea ; Holmud, Natacha Friis ; Rota, Carmen ; Stephan, Roger ; Kleta, Sylvia ; Torresi, Marina ; Laage Kragh, Martin ; Njage, Patrick Murigu Kamau ; Pagotto, Franco ; Brown, Phillip ; Fagerlund, Annette ; Langsrud, Solveig ; Szarvas, Judit ; Aboagye, Eurydice ; Huynh, TuAnh N. ; Tasara, Taurai ; Lüth, Stefanie ; Guldimann, Claudia ; Xiao, Yinghua ; Dalgaard, Paw ; Kathariou, Sophia ; Kovacevic, Jovana ; Aarestrup, Frank ; Amar, Corinne ; Pomilio, Francesco

ABSTRACTListeria monocytogenes presents a significant concern for the food industry due to its ability to persist in the food processing environment. One of the factors contributing to its persistence is decreased sensitivity to disinfectants. Our objective was to assess the diversity of L. monocytogenes sensitivity to food industry disinfectants by testing the response of 1,671 L . monocytogenes isolates to quaternary ammonium compounds (QACs) and 414 isolates to peracetic acid (PAA) using broth microdilution and growth curve analysis assays, respectively, and to categorize the isolates into sensitive and tolerant. A high phenotype-genotype concordance (95%) regarding tolerance to QACs was obtained by screening the genomes for the presence of QAC tolerance-associated genes bcrABC , emrE , emrC, and qacH . Based on this high concordance, we assessed the QAC genes’ dissemination among publicly available L. monocytogenes genomes ( n = 39,196). Overall, QAC genes were found in 23% and 28% of the L. monocytogenes collection in this study and in the global data set, respectively. bcrABC and qacH were the most prevalent genes, with bcrABC being the most detected QAC gene in the USA, while qacH dominated in Europe. No significant differences ( P > 0.05) in the PAA tolerance were detected among isolates belonging to different lineages, serogroups, clonal complexes, or isolation sources, highlighting limited variation in the L. monocytogenes sensitivity to this disinfectant. The present work represents the largest testing of L. monocytogenes sensitivity to important food industry disinfectants at the phenotypic and genomic level, revealing diversity in the tolerance to QACs while all isolates showed similar sensitivity to PAA. IMPORTANCE Contamination of Listeria monocytogenes within food processing environments is of great concern to the food industry due to challenges in eradicating the isolates once they become established and persistent in the environment. Genetic markers associated with increased tolerance to certain disinfectants have been identified, which alongside other biotic and abiotic factors can favor the persistence of L. monocytogenes in the food production environment. By employing a comprehensive large-scale phenotypic testing and genomic analysis, this study significantly enhances the understanding of the L. monocytogenes tolerance to quaternary ammonium compounds (QACs) and the genetic determinants associated with the increased tolerance. We provide a global overview of the QAC genes prevalence among public L. monocytogenes sequences and their distribution among clonal complexes, isolation sources, and geographical locations. Additionally, our comprehensive screening of the peracetic acid (PAA) sensitivity shows that this disinfectant can be used in the food industry as the lack of variation in sensitivity indicates reliable effect and no apparent possibility for the emergence of tolerance.

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SMDT1

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