High-throughput screening of a collection of known pharmacologically active small compounds for inhibitors of<i>Salmonella</i>invasion and intracellular replication

Ridge, Y.; Landini, Paolo; Thompson, Arthur R.

doi:10.1111/jam.13890

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…In-cell screens aimed at identifying chemicals that prevent pathogen intracellular replication have been described. For example screens of FDA-approved drug libraries have uncovered modulators of Listeria monocytogenes or Salmonella enterica infection [ 57 , 58 ]. Similar screens were performed with macrophages infected with Mycobacterium tuberculosis [ 59 ] or the yeast Cryptococcus neoformans [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

A cell-based infection assay identifies efflux pump modulators that reduce bacterial intracellular load

Reens

Crooks

et al. 2018

PLoS Pathog

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Bacterial efflux pumps transport small molecules from the cytoplasm or periplasm outside the cell. Efflux pump activity is typically increased in multi-drug resistant (MDR) pathogens; chemicals that inhibit efflux pumps may have potential for antibiotic development. Using an in-cell screen, we identified three efflux pump modulators (EPMs) from a drug diversity library. The screening platform uses macrophages infected with the human Gram-negative pathogen Salmonella enterica (Salmonella) to identify small molecules that prevent bacterial replication or survival within the host environment. A secondary screen for hit compounds that increase the accumulation of an efflux pump substrate, Hoechst 33342, identified three small molecules with activity comparable to the known efflux pump inhibitor PAβN (Phe-Arg β-naphthylamide). The three putative EPMs demonstrated significant antibacterial activity against Salmonella within primary and cell culture macrophages and within a human epithelial cell line. Unlike traditional antibiotics, the three compounds did not inhibit bacterial growth in standard microbiological media. The three compounds prevented energy-dependent efflux pump activity in Salmonella and bound the AcrB subunit of the AcrAB-TolC efflux system with KDs in the micromolar range. Moreover, the EPMs display antibacterial synergy with antimicrobial peptides, a class of host innate immune defense molecules present in body fluids and cells. The EPMs also had synergistic activity with antibiotics exported by AcrAB-TolC in broth and in macrophages and inhibited efflux pump activity in MDR Gram-negative ESKAPE clinical isolates. Thus, an in-cell screening approach identified EPMs that synergize with innate immunity to kill bacteria and have potential for development as adjuvants to antibiotics.

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Section: Discussionmentioning

confidence: 99%

A cell-based infection assay identifies efflux pump modulators that reduce bacterial intracellular load

Reens

Crooks

et al. 2018

PLoS Pathog

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“…Salmonella typhimurium is an important Gram-negative food-borne pathogen with a broad host range including humans and animals, and causes diseases ranging from gastroenteritis and diarrhea to life-threatening systemic infections (Wan et al, 2018), resulting in one million human deaths annually (Balasundaram et al, 2017). Owing to their metabolic versatility, Salmonella can colonize as multicellular aggregates on various surfaces, enhancing virulence levels through biofilm formations that often resist antibiotic therapy (Faccone et al, 2018; Kuang et al, 2018; Ridge et al, 2018; Wan et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Musca domestica Cecropin (Mdc) Alleviates Salmonella typhimurium-Induced Colonic Mucosal Barrier Impairment: Associating With Inflammatory and Oxidative Stress Response, Tight Junction as Well as Intestinal Flora

et al. 2019

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Salmonella typhimurium, a Gram-negative food-borne pathogen, induces impairment in intestinal mucosal barrier function frequently. The injury is related to many factors such as inflammation, oxidative stress, tight junctions and flora changes in the host intestine. Musca domestica cecropin (Mdc), a novel antimicrobial peptide containing 40 amino acids, has potential antibacterial, anti-inflammatory, and immunological functions. It remains unclear exactly whether and how Mdc reduces colonic mucosal barrier damage caused by S. typhimurium. Twenty four 6-week-old male mice were divided into four groups: normal group, control group (S. typhimurium-challenged), Mdc group, and ceftriaxone sodium group (Cs group). HE staining and transmission electron microscopy (TEM) were performed to observe the morphology of the colon tissues. Bacterial load of S. typhimurium in colon, liver and spleen were determined by bacterial plate counting. Inflammatory factors were detected by enzyme linked immunosorbent assay (ELISA). Oxidative stress levels in the colon tissues were also analyzed. Immunofluorescence analysis, RT-PCR, and Western blot were carried out to examine the levels of tight junction and inflammatory proteins. The intestinal microbiota composition was assessed via 16s rDNA sequencing. We successfully built and evaluated an S. typhimurium-infection model in mice. Morphology and microcosmic change of the colon tissues confirmed the protective qualities of Mdc. Mdc could inhibit colonic inflammation and oxidative stress. Tight junctions were improved significantly after Mdc administration. Interestingly, Mdc ameliorated intestinal flora imbalance, which may be related to the improvement of tight junction. Our results shed a new light on protective effects and mechanism of the antimicrobial peptide Mdc on colonic mucosal barrier damage caused by S. typhimurium infection. Mdc is expected to be an important candidate for S. typhimurium infection treatment.

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“…ST proliferates in the intestine, adheres to the epithelial cells of the intestinal mucosa, invades the lamina propria, and releases toxins (Matamouros and Miller, 2015). Due to its metabolic diversity, Salmonella can colonize various surfaces as multicellular aggregates and increase the level of virulence through the formation of bio lms, which are often resistant to antibiotic treatment (Faccone et al, 2018;Ridge et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Glucose oxidase exerts protective effects against Salmonella typhimurium infection by regulating the intestinal structure, immune response and cecal microbiota in murine

WANG

et al. 2022

Preprint

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Glucose oxidase (GOD), an aerobic dehydrogenase, specifically catalyzes the oxidation of β-D-glucose to gluconic acid and hydrogen peroxide, which are harmful to pathogenic bacteria but promoting the survival of beneficial bacteria in the intestine. Meanwhile, the increased antibiotic resistance induced by Salmonella typhimurium (ST) infections has amplified the need for development of novel therapeutic agents. As such, GOD may play an important role in controlling ST infections. To investigate the effects of GOD against ST infection, mice were pretreated with gentamicin (GM; positive control), GOD, or sterile water (negative control) and, four weeks later, challenged with ST or phosphate-buffered saline. Three days after infection, mice were sacrificed and samples were collected. In the present study, pretreatment with GOD or GM attenuated ST-induced body weight loss and mortality. Moreover, ST infection increased the intestinal damage, apoptosis in liver, inflammatory response in the colon and serum, which were reversed by GOD pretreatment. Sequence analysis further revealed that the gut bacterial community composition in mice pretreated with GOD was similar to that of the control group. Collectively, these findings indicate that GOD attenuates ST-induced negative effects by modulating intestinal barrier function, cytokine secretion, and intestinal microbiota composition in mice.

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High-throughput screening of a collection of known pharmacologically active small compounds for inhibitors ofSalmonellainvasion and intracellular replication

Abstract: The emergence of multidrug-resistant strains of Salmonella poses a considerable and growing worldwide threat to human and animal health. The screening of off-patent chemical libraries represents a potential discovery route for novel antimicrobials.

Cited by 4 publications

References 31 publications

A cell-based infection assay identifies efflux pump modulators that reduce bacterial intracellular load

A cell-based infection assay identifies efflux pump modulators that reduce bacterial intracellular load

Musca domestica Cecropin (Mdc) Alleviates Salmonella typhimurium-Induced Colonic Mucosal Barrier Impairment: Associating With Inflammatory and Oxidative Stress Response, Tight Junction as Well as Intestinal Flora

Glucose oxidase exerts protective effects against Salmonella typhimurium infection by regulating the intestinal structure, immune response and cecal microbiota in murine

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