Still rocking in the structural era: A molecular overview of the small multidrug resistance (SMR) transporter family

Burata, Olive E.; Yeh, Trevor Justin; Macdonald, Christian B.; Stockbridge, Randy B.

doi:10.1016/j.jbc.2022.102482

Cited by 23 publications

(22 citation statements)

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“…Multidrug resistance (MDR) transporters actively efflux polyaromatic cations, quaternary ammonium compounds, and other toxic small molecules, reducing intracellular concentrations sufficiently to enable bacterial survival. The small multidrug resistance (SMR) transporters are the smallest known active transporters and are found primarily in bacteria, although they have also been reported in archaea and most recently in fungi (Bay & Turner, 2016; Burata et al., 2022; Kermani et al., 2018; Ninio & Schuldiner, 2003; Seppälä et al., 2023). Several studies have implicated SMR transporters in a variety of bacterial processes in addition to toxin efflux, including biofilm production (Andremont et al., 2010; Bay et al., 2017; Willsey et al., 2018), osmotic stress regulation (Bay & Turner, 2012), and toxic metabolite transport (Higashi et al., 2008; Higgins et al., 2019; Kermani et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

“…Other members of the SMR family have been identified through sequence analysis (Kermani et al., 2018; Lolkema et al., 1998; Nelson et al., 2017) and have been divided into four subtypes based on sequence, substrates, and regulatory elements as recently reviewed in (Burata et al., 2022). Since experimental assessment of transport or antimicrobial resistance phenotypes has only been performed for a relatively small number of SMR homologs and a limited number of substrates, this classification is ongoing (Bay & Turner, 2012, 2016; Brill et al., 2012; Kermani et al., 2018; Lytvynenko et al., 2016; Mitchell et al., 2019; Nasie et al., 2012; Saleh et al., 2018).…”

Section: Introductionmentioning

confidence: 99%

“…EmrE from E. coli was the first SMR transporter to be functionally characterized both in vitro and in vivo and is still the most extensively studied SMR homolog (Burata et al, 2022;Yerushalmi et al, 1995). EmrE functions as an antiparallel homodimer and is a highly promiscuous transporter that exports quaternary ammonium compounds, polyaromatic cations, dyes, and planar toxins across the inner membrane of E. coli (Bay et al, 2017;Morrison et al, 2012Morrison et al, , 2015Saleh et al, 2018;Yerushalmi et al, 1995).…”

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confidence: 99%

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Functional promiscuity of small multidrug resistance transporters from Staphylococcus aureus, Pseudomonas aeruginosa, and Francisella tularensis

Spreacker,

Wegrzynowicz,

Porter

et al. 2024

Molecular Microbiology

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Small multidrug resistance transporters efflux toxic compounds from bacteria and are a minimal system to understand multidrug transport. Most previous studies have focused on EmrE, the model SMR from Escherichia coli, finding that EmrE has a broader substrate profile than previously thought and that EmrE may perform multiple types of transport, resulting in substrate‐dependent resistance or susceptibility. Here, we performed a broad screen to identify potential substrates of three other SMRs: PAsmr from Pseudomonas aeruginosa; FTsmr from Francisella tularensis; and SAsmr from Staphylococcus aureus. This screen tested metabolic differences in E. coli expressing each transporter versus an inactive mutant, for a clean comparison of sequence and substrate‐specific differences in transporter function, and identified many substrates for each transporter. In general, resistance compounds were charged, and susceptibility substrates were uncharged, but hydrophobicity was not correlated with phenotype. Two resistance hits and two susceptibility hits were validated via growth assays and IC50 calculations. Susceptibility is proposed to occur via substrate‐gated proton leak, and the addition of bicarbonate antagonizes the susceptibility phenotype, consistent with this hypothesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional promiscuity of small multidrug resistance transporters from Staphylococcus aureus, Pseudomonas aeruginosa, and Francisella tularensis

Spreacker,

Wegrzynowicz,

Porter

et al. 2024

Molecular Microbiology

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“…Understanding how compounds interact with transporters is crucial in the field of drug development targeting transporters [62]. Equally, it sheds light on the pharmacokinetic attributes and drug-drug interactions of potential pharmaceutical candidates [63][64][65]. In this investigation, we created diverse transporter inhibitor predictive models, employing both conventional machine learning techniques and advanced deep learning methods.…”

Section: Discussionmentioning

confidence: 99%

In Silicoprediction of inhibitors for multiple transporters via machine learning methods

Duan,

Lou,

et al. 2024

Molecular Informatics

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Transporters play an indispensable role in facilitating the transport of nutrients, signaling molecules and the elimination of metabolites and toxins in human cells. Contemporary computational methods have been employed in the prediction of transporter inhibitors. However, these methods often focus on isolated endpoints, overlooking the interactions between transporters and lacking good interpretation. In this study, we integrated a comprehensive dataset and constructed models to assess the inhibitory effects on seven transporters. Both conventional machine learning and multi‐task deep learning methods were employed. The results demonstrated that the MLT‐GAT model achieved superior performance with an average AUC value of 0.882. It is noteworthy that our model excels not only in prediction performance but also in achieving robust interpretability, aided by GNN‐Explainer. It provided valuable insights into transporter inhibition. The reliability of our model's predictions positioned it as a promising and valuable tool in the field of transporter inhibition research. Related data and code were available at https://gitee.com/wutiantian99/transporter_code.git

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“…As a charged molecule, it would need a dedicated mechanism to translocate from inside the cell into the medium. Genome sequencing had identified two contiguous and identical genes encoding SugE family proteins known as Gdx transporters, that export quaternary amine and guanidinium compounds, although none, to our knowledge, had previously been shown to transport guanylurea (Chung and Saier, 2002;Burata et al, 2022). To assess whether the plasmid-borne Aminobacter Gdx transporter exports guanylurea, we heterologously expressed, purified, and reconstituted this protein in proteoliposomes (Supplementary Figure S2).…”

Section: Identification and Metabolic Characterization Of Aminobacter...mentioning

confidence: 99%

Wastewater bacteria remediating the pharmaceutical metformin: Genomes, plasmids and products

Martinez‐Vaz

Dodge

Lucero

et al. 2022

Front. Bioeng. Biotechnol.

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Metformin is used globally to treat type II diabetes, has demonstrated anti-ageing and COVID mitigation effects and is a major anthropogenic pollutant to be bioremediated by wastewater treatment plants (WWTPs). Metformin is not adsorbed well by activated carbon and toxic N-chloro derivatives can form in chlorinated water. Most earlier studies on metformin biodegradation have used wastewater consortia and details of the genomes, relevant genes, metabolic products, and potential for horizontal gene transfer are lacking. Here, two metformin-biodegrading bacteria from a WWTP were isolated and their biodegradation characterized. Aminobacter sp. MET metabolized metformin stoichiometrically to guanylurea, an intermediate known to accumulate in some environments including WWTPs. Pseudomonasmendocina MET completely metabolized metformin and utilized all the nitrogen atoms for growth. Pseudomonas mendocina MET also metabolized metformin breakdown products sometimes observed in WWTPs: 1-N-methylbiguanide, biguanide, guanylurea, and guanidine. The genome of each bacterium was obtained. Genes involved in the transport of guanylurea in Aminobacter sp. MET were expressed heterologously and shown to serve as an antiporter to expel the toxic guanidinium compound. A novel guanylurea hydrolase enzyme was identified in Pseudomonas mendocina MET, purified, and characterized. The Aminobacter and Pseudomonas each contained one plasmid of 160 kb and 90 kb, respectively. In total, these studies are significant for the bioremediation of a major pollutant in WWTPs today.

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Still rocking in the structural era: A molecular overview of the small multidrug resistance (SMR) transporter family

Cited by 23 publications

References 151 publications

Functional promiscuity of small multidrug resistance transporters from Staphylococcus aureus, Pseudomonas aeruginosa, and Francisella tularensis

Functional promiscuity of small multidrug resistance transporters from Staphylococcus aureus, Pseudomonas aeruginosa, and Francisella tularensis

In Silicoprediction of inhibitors for multiple transporters via machine learning methods

Wastewater bacteria remediating the pharmaceutical metformin: Genomes, plasmids and products

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