In Vitro Models for the Study of the Intracellular Activity of Antibiotics

Peyrusson, Frédéric; Nguyen, Tiep Khac; Buyck, Julien; Lemaire, Sandrine; Wang, Gang; Seral, Cristina; Tulkens, Paul M.; Bambeke, Françoise Van

doi:10.1007/978-1-0716-1621-5_16

Cited by 4 publications

(4 citation statements)

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“…Considering first antibiotic potency, we observed that Cs was close to the respective MIC (1.5 to 4 x the MIC) in all cases, as previously described in other models of intracellular infection (31,60,61), and independently of the capacity of the drug to accumulate inside monocytes (Table S1) (62,63). This is interpreted as denoting a poor intracellular bioavailability (61). Although gain in potency is a pharmacokinetic-driven parameter, meaning that it essentially reflects a change in the antibiotic concentration needed to reach a specified effect (bacteriostatic effect for Cs (61)), it was not related to the lipophilicity of the antibiotic (Figure S8A).…”

Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 82%

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The polyamino-isoprenyl potentiator NV716 revives disused antibiotics against Gram-negative bacteria in broth, infected monocytes, or biofilms, by disturbing the barrier effect of their outer membrane

Wang

Brunel

Rodríguez-Villalobos

et al. 2022

European Journal of Medicinal Chemistry

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 82%

The polyamino-isoprenyl potentiator NV716 revives disused antibiotics against Gram-negative bacteria in broth, infected monocytes, or biofilms, by disturbing the barrier effect of their outer membrane

Wang

Brunel

Rodríguez-Villalobos

et al. 2022

European Journal of Medicinal Chemistry

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“… 1 The avidity of this pathogen to be rapidly internalized by host cells imposes a barrier for commonly used antibiotics, which are more effective in extracellular locations. 2 , 3 Many studies have shown limited accessibility of drugs to the intracellular niche occupied by the pathogen, a factor decreasing their inhibitory activity. 3 In intraphagosomal intracellular pathogens, other factors such the acidity of the compartment colonized by the pathogen can also affect antibiotic activity.…”

Section: Introductionmentioning

confidence: 99%

“… 2 , 3 Many studies have shown limited accessibility of drugs to the intracellular niche occupied by the pathogen, a factor decreasing their inhibitory activity. 3 In intraphagosomal intracellular pathogens, other factors such the acidity of the compartment colonized by the pathogen can also affect antibiotic activity. To counterbalance these negative effects, new approaches based on highly penetrating nanoparticles carrying the drug as cargo are currently under intense investigation and development.…”

Section: Introductionmentioning

confidence: 99%

Affinity of cefotiam for the alternative penicillin binding protein PBP3SAL used by Salmonella inside host eukaryotic cells

Cestero

Castanheira

González

et al. 2022

Journal of Antimicrobial Chemotherapy

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Background Following the invasion of eukaryotic cells, Salmonella enterica serovar Typhimurium replaces PBP2/PBP3, main targets of β-lactam antibiotics, with PBP2SAL/PBP3SAL, two homologue peptidoglycan synthases absent in Escherichia coli. PBP3SAL promotes pathogen cell division in acidic environments independently of PBP3 and shows low affinity for β-lactams that bind to PBP3 such as aztreonam, cefepime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime and cefalotin. Objectives To find compounds with high affinity for PBP3SAL to control Salmonella intracellular infections. Methods An S. Typhimurium ΔPBP3 mutant that divides using PBP3SAL and its parental wild-type strain, were exposed to a library of 1520 approved drugs in acidified (pH 4.6) nutrient-rich LB medium. Changes in optical density associated with cell filamentation, a read-out of blockage in cell division, were monitored. Compounds causing filamentation in the ΔPBP3 mutant but not in wild-type strain—the latter strain expressing both PBP3 and PBP3SAL in LB pH 4.6—were selected for further study. The bactericidal effect due to PBP3SAL inhibition was evaluated in vitro using a bacterial infection model of cultured fibroblasts. Results The cephalosporin cefotiam exhibited higher affinity for PBP3SAL than for PBP3 in bacteria growing in acidified LB pH 4.6 medium. Cefotiam also proved to be effective against intracellular Salmonella in a PBP3SAL-dependent manner. Conversely, cefuroxime, which has higher affinity for PBP3, showed decreased effectiveness in killing intracellular Salmonella. Conclusions Antibiotics with affinity for PBP3SAL, like the cephalosporin cefotiam, have therapeutic value for treating Salmonella intracellular infections.

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Comparative in vitro efficacy of antibiotics against the intracellular reservoir of Staphylococcus aureus

Beadell,

Yamauchi,

Wong-Beringer

2024

Journal of Antimicrobial Chemotherapy

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Staphylococcus aureus (SA) is a leading cause of bloodstream infection. The liver represents the sentinel immune organ for clearance of bloodstream pathogens and eradication of intracellular SA from liver-resident macrophages (Kupffer cells, KCs) eliminates the likely pathogenic reservoir that contributes to persistent bacteraemia. Objectives We assessed antimicrobial activity at phagolysosome-mimicking pH, intracellular penetration, and SA eradication within KCs in vitro for clinically prescribed antistaphylococcal agents alone or in combination: vancomycin, daptomycin, ceftaroline, ceftobiprole, oritavancin, oxacillin, cefazolin; rifampin and fosfomycin. Methods pH-adjusted broth microdilution assays, intracellular bioaccumulation assays, and intracellular killing assays against clinical bloodstream isolates were performed using a murine KC line with study agents. Results Rifampin and β-lactams exhibited enhanced activity [2- to 16-fold minimum inhibitory concentrations (MIC) decrease] at phagolysosomal pH while vancomycin, oritavancin, daptomycin and fosfomycin demonstrated reduced activity (2- to 32-fold MIC increase in order of least to greatest potency reduction). All agents evaluated had poor to modest intracellular to extracellular concentration ratios (0.024–7.8), with exceptions of rifampin and oritavancin (intracellular to extracellular ratios of 17.4 and 78.2, respectively). Finally, we showed that the first-line treatment for SA bacteraemia (SAB), vancomycin, performed worse than all other tested antibiotics in eradicating intracellular SA at human Cmax concentration (0.20 log cfu decrease), while oritavancin performed better than all other agents alone (2.05 versus 1.06–1.36 log cfu decrease). Conclusions Our findings raise concerns about the efficacy of commonly prescribed antibiotics against intracellular SA reservoirs and emphasize the need to consider targeting pathogen eradication from the liver to achieve early control of SAB.

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In Vitro Models for the Study of the Intracellular Activity of Antibiotics

Abstract: The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

Cited by 4 publications

References 36 publications

The polyamino-isoprenyl potentiator NV716 revives disused antibiotics against Gram-negative bacteria in broth, infected monocytes, or biofilms, by disturbing the barrier effect of their outer membrane

The polyamino-isoprenyl potentiator NV716 revives disused antibiotics against Gram-negative bacteria in broth, infected monocytes, or biofilms, by disturbing the barrier effect of their outer membrane

Affinity of cefotiam for the alternative penicillin binding protein PBP3SAL used by Salmonella inside host eukaryotic cells

Comparative in vitro efficacy of antibiotics against the intracellular reservoir of Staphylococcus aureus

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