scholarly journals Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. T. Heemskerk ◽  
C. J. Korbee ◽  
J. J. Esselink ◽  
C. Carvalho dos Santos ◽  
S. van Veen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Salmonella Enterica ◽  
Antipsychotic Drugs ◽  
Growth Control ◽  
Multidrug Resistant ◽  
Oxidative Stress Response ◽  
Intracellular Pathogen ◽  
Inhibitory Effects ◽  
Serovar Typhimurium ◽  
Host Signaling

AbstractThe persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide’s and Fluspirilene’s efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

scholarly journals Repurposing diphenylbutylpiperidine-class antipsychotic drugs for host-directed therapy of Mycobacterium tuberculosis and Salmonella enterica infections

2021 ◽  
Author(s):  
Matthias T Heemskerk ◽  
Cornelis J Korbee ◽  
Jeroen Esselink ◽  
Carina Carvalho dos Santos ◽  
Suzanne van Veen ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Salmonella Enterica ◽  
Antipsychotic Drugs ◽  
Growth Control ◽  
Multidrug Resistant ◽  
Intracellular Pathogen ◽  
Inhibitory Effects ◽  
Tb Treatment ◽  
Serovar Typhimurium ◽  
Host Signaling

The persistent increase of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) infections negatively impacts Tuberculosis (TB) treatment outcomes. Host-directed therapies (HDT) pose an complementing strategy, particularly since Mtb is highly successful in evading host-defense by manipulating host-signaling pathways. Here, we screened a library containing autophagy-modulating compounds for their ability to inhibit intracellular Mtb-bacteria. Several active compounds were identified, including two drugs of the diphenylbutylpiperidine-class, Fluspirilene and Pimozide, commonly used as antipsychotics. Both molecules inhibited intracellular Mtb in pro- as well as anti-inflammatory primary human macrophages in a host-directed manner and synergized with conventional anti-bacterials. Importantly, these inhibitory effects extended to MDR-Mtb strains and the unrelated intracellular pathogen, Salmonella enterica serovar Typhimurium (Stm). Mechanistically Fluspirilene and Pimozide were shown to regulate autophagy and alter the lysosomal response, partly correlating with increased bacterial localization to autophago(lyso)somes. Pimozide's and Fluspirilene's efficacy was inhibited by antioxidants, suggesting involvement of the oxidative-stress response in Mtb growth control. Furthermore, Fluspirilene and especially Pimozide counteracted Mtb-induced STAT5 phosphorylation, thereby reducing Mtb phagosome-localized CISH that promotes phagosomal acidification. In conclusion, two approved antipsychotic drugs, Pimozide and Fluspirilene, constitute highly promising and rapidly translatable candidates for HDT against Mtb and Stm and act by modulating the autophagic/lysosomal response by multiple mechanisms.

scholarly journals Characterization of Salmonella enterica Serovar Typhimurium from Marine Environments in Coastal Waters of Galicia (Spain)

2004 ◽  
Vol 70 (7) ◽  
pp. 4030-4034 ◽  
Author(s):  
Jaime Martinez-Urtaza ◽  
Ernesto Liebana ◽  
Lourdes Garcia-Migura ◽  
Pelayo Perez-Piñeiro ◽  
Montserrat Saco
Keyword(s):  
Coastal Waters ◽  
Salmonella Enterica ◽  
Multidrug Resistant ◽  
Marine Environments ◽  
Pfge Analysis ◽  
Phage Types ◽  
Plasmid Analysis ◽  
Routine Surveillance ◽  
Serovar Typhimurium ◽  
Plasmid Profiling

ABSTRACT Twenty-three Salmonella enterica serovar Typhimurium isolates from marine environments were characterized by phage typing, pulsed-field gel electrophoresis (PFGE) analysis, plasmid analysis, and antibiotic resistance, and the distribution of the different types in the coastal waters were subsequently analyzed. Five phage types were identified among the isolates (PT41, PT135, PT99, DT104, and DT193). PT135 isolates were exclusively detected during the winter months from 1998 to 2000, whereas DT104 and PT41 isolates were detected exclusively in the summer months from 2000 to 2002. XbaI PFGE analysis revealed 9 PFGE types, and plasmid profiling identified 8 plasmid types (with 1 to 6 plasmids) among the isolates. Only three isolates presented multidrug resistance to antibiotics. Two DT104 isolates were resistant to 8 and 7 antibiotics (profiles ACCeFNaSSuT and ACeFNeSSuT), whereas a PT193 isolate presented resistance to 6 antibiotics (profile ACFSSu). In addition, four PT41 isolates were resistant to a single antibiotic. The detection of multidrug-resistant phage types DT104 and DT193 in shellfish emphasizes the importance of monitoring the presence of Salmonella in routine surveillance of live bivalve molluscs.

scholarly journals In Vitro and In Vivo Assessment of Salmonella enterica Serovar Typhimurium DT104 Virulence

2001 ◽  
Vol 69 (7) ◽  
pp. 4673-4677 ◽  
Author(s):  
Chris A. Allen ◽  
Paula J. Fedorka-Cray ◽  
Andrés Vazquez-Torres ◽  
Mitsu Suyemoto ◽  
Craig Altier ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Phage Type ◽  
Multidrug Resistant ◽  
Peritoneal Macrophages ◽  
Lethal Infection ◽  
Animal Infection ◽  
Serovar Typhimurium ◽  
Clinical Illness

ABSTRACT Multidrug-resistant Salmonella enterica serovar Typhimurium phage type DT104 has become a widespread cause of human and other animal infection worldwide. The severity of clinical illness inS. enterica serovar Typhimurium DT104 outbreaks has led to the suggestion that this strain possesses enhanced virulence. In the present study, in vitro and in vivo virulence-associated phenotypes of several clinical isolates of S. enterica serovar Typhimurium DT104 were examined and compared to S. entericaserovar Typhimurium ATCC 14028s. The ability of these DT104 isolates to survive within murine peritoneal macrophages, invade cultured epithelial cells, resist antimicrobial actions of reactive oxygen and nitrogen compounds, and cause lethal infection in mice were assessed. Our results failed to demonstrate that S. enterica serovar Typhimurium DT104 isolates are more virulent than S. enterica serovar Typhimurium ATCC 14028s.

scholarly journals Alterations of Salmonella enterica Serovar Typhimurium Antibiotic Resistance under Environmental Pressure

2018 ◽  
Vol 84 (19) ◽  
Author(s):  
Mengfei Peng ◽  
Serajus Salaheen ◽  
Robert L. Buchanan ◽  
Debabrata Biswas
Keyword(s):  
Antibiotic Resistance ◽  
Resistance Genes ◽  
Salmonella Enterica ◽  
Tetracycline Resistance ◽  
Multidrug Resistant ◽  
Genetic Alterations ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Farm Systems ◽  
Serovar Typhimurium

ABSTRACT Microbial horizontal gene transfer is a continuous process that shapes bacterial genomic adaptation to the environment and the composition of concurrent microbial ecology. This includes the potential impact of synthetic antibiotic utilization in farm animal production on overall antibiotic resistance issues; however, the mechanisms behind the evolution of microbial communities are not fully understood. We explored potential mechanisms by experimentally examining the relatedness of phylogenetic inference between multidrug-resistant Salmonella enterica serovar Typhimurium isolates and pathogenic Salmonella Typhimurium strains based on genome-wide single-nucleotide polymorphism (SNP) comparisons. Antibiotic-resistant S. Typhimurium isolates in a simulated farm environment barely lost their resistance, whereas sensitive S. Typhimurium isolates in soils gradually acquired higher tetracycline resistance under antibiotic pressure and manipulated differential expression of antibiotic-resistant genes. The expeditious development of antibiotic resistance and the ensuing genetic alterations in antimicrobial resistance genes in S. Typhimurium warrant effective actions to control the dissemination of Salmonella antibiotic resistance. IMPORTANCE Antibiotic resistance is attributed to the misuse or overuse of antibiotics in agriculture, and antibiotic resistance genes can also be transferred to bacteria under environmental stress. In this study, we report a unidirectional alteration in antibiotic resistance from susceptibility to increased resistance. Highly sensitive Salmonella enterica serovar Typhimurium isolates from organic farm systems quickly acquired tetracycline resistance under antibiotic pressure in simulated farm soil environments within 2 weeks, with expression of antibiotic resistance-related genes that was significantly upregulated. Conversely, originally resistant S. Typhimurium isolates from conventional farm systems lost little of their resistance when transferred to environments without antibiotic pressure. Additionally, multidrug-resistant S. Typhimurium isolates genetically shared relevancy with pathogenic S. Typhimurium isolates, whereas susceptible isolates clustered with nonpathogenic strains. These results provide detailed discussion and explanation about the genetic alterations and simultaneous acquisition of antibiotic resistance in S. Typhimurium in agricultural environments.

scholarly journals Isolation and Characterization of Salmonella Enterica Serovar Typhimurium Circulating Among Healthy Chickens of Bangladesh

2016 ◽  
Vol 4 (7) ◽  
pp. 519
Author(s):  
Md. Shafiullah Parvej ◽  
Marzia Rahman ◽  
Md. Forhad Uddin ◽  
KHM Nazmul Hussain Nazir ◽  
Md. Sayduzzaman Jowel ◽  
...  
Keyword(s):  
Salmonella Enterica ◽  
Salmonella Enterica Serovar Typhimurium ◽  
Multidrug Resistant ◽  
Cloacal Swab ◽  
Specific Gene ◽  
Isolation And Characterization ◽  
Serovar Typhimurium ◽  
Salmonella Serovars ◽  
Layer Chickens ◽  
Apparently Healthy

Salmonella is considered as a global problem ranking first among food borne diseases. All motile Salmonella of poultry origin are zoonotic and readily transmit to human via meat and eggs but reports on non - typhoidal Salmonella serovars circulating in layer chickens is very limited in South-East Asian countries including Bangladesh. Salmonella serovars isolated from apparently healthy chickens were characterized in the present study. Of 170 samples (cloacal swab 150 and feed 20) collected from commercial layer farms, motile Salmonella was isolated 4% (6/150) and 50% (10/20) respectively by cultural, biochemical, motility test and by detection of hisJ gene. About 5% (8/170) samples possessed serovar-specific gene fimA, suggesting that isolates were Salmonella enterica serovar Typhimurium. Antimicrobial susceptibility testing demonstrated that the isolated serovars were multidrug resistant. Therefore apparently healthy layer chickens harbour and transmit S. Typhimurium to the environment, although little is alarming since it has zoonotic significance and the isolates were resistant to commonly used first line of antibiotic in Salmonella infection.

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