A cell-based approach to characterize antimicrobial compounds through kinetic dose response

MacNair, Craig R.; Stokes, Jonathan; French, Shawn; Myers, Cullen L.; Iyer, Kali R.; Brown, Eric D.

doi:10.1016/j.bmc.2016.09.053

Cited by 7 publications

(4 citation statements)

References 24 publications

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“…2a, b ). The observed change in lytic susceptibility appears to be polymyxin specific, as lysis by ampicillin occurs as previously described 32 for both strains (Supplementary Fig. 2c ).…”

Section: Resultssupporting

confidence: 81%

Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics

et al. 2018

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Plasmid-borne colistin resistance mediated by mcr-1 may contribute to the dissemination of pan-resistant Gram-negative bacteria. Here, we show that mcr-1 confers resistance to colistin-induced lysis and bacterial cell death, but provides minimal protection from the ability of colistin to disrupt the Gram-negative outer membrane. Indeed, for colistin-resistant strains of Enterobacteriaceae expressing plasmid-borne mcr-1, clinically relevant concentrations of colistin potentiate the action of antibiotics that, by themselves, are not active against Gram-negative bacteria. The result is that several antibiotics, in combination with colistin, display growth-inhibition at levels below their corresponding clinical breakpoints. Furthermore, colistin and clarithromycin combination therapy displays efficacy against mcr-1-positive Klebsiella pneumoniae in murine thigh and bacteremia infection models at clinically relevant doses. Altogether, these data suggest that the use of colistin in combination with antibiotics that are typically active against Gram-positive bacteria poses a viable therapeutic alternative for highly drug-resistant Gram-negative pathogens expressing mcr-1.

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“…2a, b ). The observed change in lytic susceptibility appears to be polymyxin specific, as lysis by ampicillin occurs as previously described 32 for both strains (Supplementary Fig. 2c ).…”

Section: Resultssupporting

confidence: 81%

Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics

et al. 2018

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“…This approach has been shown to generate unique dose response profiles for different antimicrobial agents, providing insight into mechanisms of bactericidal or bacteriostatic activity. 29 In the presence of AZT at near-MIC concentrations, ST313 iNTS had an increased lag time, reduced replication, and decreased maximum optical density ( Fig. 2d ).…”

Section: Resultsmentioning

confidence: 90%

Screening under infection-relevant conditions reveals chemical sensitivity in multidrug resistant invasive non-typhoidal Salmonella (iNTS)

et al. 2023

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“…To gain further insight into the mechanism of AZT activity, we monitored the growth of ST313 in the presence of AZT at sub-inhibitory concentrations during overnight incubation. This approach has been shown to generate unique dose response profiles for different antimicrobial agents, providing insight into mechanisms of bactericidal or bacteriostatic activity (27). In the presence of AZT at near-MIC concentrations (1 μg/mL and below), ST313 iNTS had an increased lag time, reduced replication, and decreased maximum optical density ( Figure 2d ).…”

Section: Resultsmentioning

confidence: 99%

Screening under infection-relevant conditions reveals chemical sensitivity in multidrug resistant invasive non-typhoidal Salmonella (iNTS)

Tsai

Massicotte

MacNair

et al. 2022

Preprint

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Bloodstream infections caused by invasive, non-typhoidal salmonellae (iNTS) are a major global health concern. These infections are especially problematic in sub-Saharan Africa, where the sequence type (ST) 313 of invasive non-typhoidal Salmonella Typhimurium (iNTS) is dominant. Unlike S. Typhimurium strains that cause mild gastroenteritis, iNTS strains are resistant to multiple first-line antibiotics and have higher extraintestinal invasiveness, limiting current treatment options. Here, we performed multiple small molecule screens under infection-relevant conditions to reveal chemical sensitivities in ST313 as entry points to drug discovery to combat the clinical burden of iNTS. By screening the invasive ST313 sequence type under host-mimicking conditions, we identified the antimicrobial activity of the nucleoside analog 3’-azido-3’-deoxythymidine, which required bacterial thymidine kinase activity for its antimicrobial activity. In a parallel macrophage-based screening platform, we also identified three host-directed compounds (amodiaquine, berbamine, and indatraline) that significantly restricted intracellular replication of ST313 in macrophages without directly impacting bacterial viability. This work provides evidence that despite elevated invasiveness and multidrug resistance, iNTS S. Typhimurium remains susceptible to unconventional drug discovery approaches.

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A cell-based approach to characterize antimicrobial compounds through kinetic dose response

Cited by 7 publications

References 24 publications

Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics

Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics

Screening under infection-relevant conditions reveals chemical sensitivity in multidrug resistant invasive non-typhoidal Salmonella (iNTS)

Screening under infection-relevant conditions reveals chemical sensitivity in multidrug resistant invasive non-typhoidal Salmonella (iNTS)

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