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15 pages, 5888 KB

Open AccessArticle

Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli

by Alessio Atzori, Giuliano Malloci, Francesca Cardamone, Andrea Bosin, Attilio Vittorio Vargiu and Paolo Ruggerone

Int. J. Mol. Sci. 2020, 21(3), 860; https://doi.org/10.3390/ijms21030860 - 29 Jan 2020

Cited by 12 | Viewed by 4303

Abstract

The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of Escherichia coli and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are known to be AcrB substrates, only a few co-crystal structures are available to date. Computational methods have been therefore intensively employed to provide structural and dynamical fingerprints related to transport and inhibition of AcrB. In this work, we performed a systematic computational investigation to study the interaction between representative carbapenem antibiotics and AcrB. We focused on the interaction of carbapenems with the so-called distal pocket, a region known for its importance in binding inhibitors and substrates of AcrB. Our findings reveal how the different physico-chemical nature of these antibiotics is reflected on their binding preference for AcrB. The molecular-level information provided here could help design new antibiotics less susceptible to the efflux mechanism. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)

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25 pages, 5960 KB

Open AccessArticle

Achillin Increases Chemosensitivity to Paclitaxel, Overcoming Resistance and Enhancing Apoptosis in Human Hepatocellular Carcinoma Cell Line Resistant to Paclitaxel (Hep3B/PTX)

by Jessica Nayelli Sanchez-Carranza, Leticia González-Maya, Rodrigo Said Razo-Hernández, Enrique Salas-Vidal, Ninfa Yaret Nolasco-Quintana, Aldo F. Clemente-Soto, Lucero García-Arizmendi, Mariana Sánchez-Ramos, Silvia Marquina and Laura Alvarez

Pharmaceutics 2019, 11(10), 512; https://doi.org/10.3390/pharmaceutics11100512 - 4 Oct 2019

Cited by 17 | Viewed by 4739

Abstract

Multidrug resistance (MDR) has become a major obstacle in the treatment of cancer, and is associated with mechanisms such as increased drug outflow, reduction of apoptosis, and/or altered drug metabolism. These problems can be mitigated by the coadministration of agents known as chemosensitizers, as they can reverse resistance to anticancer drugs and eventually resensitize cancer cells. We explore the chemosensitizing effect of Achillin, a guaianolide-type sesquiterpene lactone isolated from the Mexican medicinal plant Artemisia ludovisiana, to reverse MDR in Hep3B/PTX cells of hepatocellular carcinoma, which present resistance to paclitaxel (PTX). Achillin showed an important effect as chemosensitizer; indeed, the cytotoxic effect of PTX (25 nM) was enhanced, and the induction of G2/M phase cell cycle arrest and apoptosis were potentiated when combining with Achillin (100 μM). In addition, we observed that Achillin decreases P-gp levels and increases the intracellular retention of doxorubicin in Hep3B/PTX cells; in addition, homology structural modeling and molecular docking calculations predicted that Achillin interacts in two regions (M-site and R-site) of transporter drug efflux P-glycoprotein (P-gp). Our results suggest that the chemosensitizer effect demonstrated for Achillin could be associated with P-gp modulation. This work also provides useful information for the development of new therapeutic agents from guaianolide-type sesquiterpene lactones like Achillin. Full article

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10 pages, 1356 KB

Open AccessArticle

Genomic Sequence Analysis of the Multidrug-Resistance Region of Avian Salmonella enterica serovar Indiana Strain MHYL

by Yan Lu, Yanjia Wen, Ge Hu, Yuqi Liu, Ross C. Beier and Xiaolin Hou

Microorganisms 2019, 7(8), 248; https://doi.org/10.3390/microorganisms7080248 - 9 Aug 2019

Cited by 5 | Viewed by 4004

Abstract

A series of human and animal diseases that are caused by Salmonella infections pose a serious threat to human health and huge economic losses to the livestock industry. We found antibiotic resistance (AR) genes in the genome of 133 strains of S. Indiana from a poultry production site in Shandong Province, China. Salmonella enterica subsp. enterica serovar Indiana strain MHYL had multidrug-resistance (MDR) genes on its genome. Southern blot analysis was used to locate genes on the genomic DNA. High-throughput sequencing technology was used to determine the gene sequence of the MHYL genome. Areas containing MDR genes were mapped based on the results of gene annotation. The AR genes bla_TEM, strA, tetA, and aac(6′)-Ib-cr were found on the MHYL genome. The resistance genes were located in two separate MDR regions, RR1 and RR2, containing type I integrons, and Tn7 transposons and multiple IS26 complex transposons with transposable functions. Portions of the MDR regions were determined to be highly homologous to the structure of plasmid pAKU_1 in S. enterica serovar Paratyphi A (accession number: AM412236), SGI11 in S. enterica serovar Typhimurium (accession number: KM023773), and plasmid pS414 in S. Indiana (accession No.: KC237285). Full article

(This article belongs to the Special Issue Foodborne Pathogen Distribution, Ecology, Inactivation and Methods of Differentiation)

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17 pages, 8364 KB

Open AccessArticle

Genetic Structure and Molecular Variability Analysis of Citrus sudden death-associated virus Isolates from Infected Plants Grown in Brazil

by Emilyn Emy Matsumura, Helvécio Della Coletta Filho, Silvia De Oliveira Dorta, Shahideh Nouri and Marcos Antonio Machado

Viruses 2016, 8(12), 330; https://doi.org/10.3390/v8120330 - 16 Dec 2016

Cited by 9 | Viewed by 5469

Abstract

Citrus sudden death-associated virus (CSDaV) is a monopartite positive-sense single-stranded RNA virus that was suggested to be associated with citrus sudden death (CSD) disease in Brazil. Here, we report the first study of the genetic structure and molecular variability among 31 CSDaV isolates collected from both symptomatic and asymptomatic trees in CSD-affected areas. Analyses of partial nucleotide sequences of five domains of the CSDaV genomic RNA, including those encoding for the methyltransferase, the multi-domain region (MDR), the helicase, the RNA-dependent RNA polymerase and the coat protein, showed that the MDR coding region was the most diverse region assessed here, and a possible association between this region and virus adaption to different host or plant tissues is considered. Overall, the nucleotide diversity (π) was low for CSDaV isolates, but the phylogenetic analyses revealed the predominance of two main groups, one of which showed a higher association with CSD-symptomatic plants. Isolates obtained from CSD-symptomatic plants, compared to those obtained from asymptomatic plants, showed higher nucleotide diversity, nonsynonymous and synonymous substitution rates and number of amino acid changes on the coding regions located closer to the 5’ end region of the genomic RNA. This work provides new insights into the genetic diversity of the CSDaV, giving support for further epidemiological studies. Full article

(This article belongs to the Section Viruses of Plants, Fungi and Protozoa)

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