Staphylococcal Bacterial Persister Cells, Biofilms, and Intracellular Infection Are Disrupted by JD1, a Membrane-Damaging Small Molecule

Dombach, Jamie L.; Quintana, Joaquin L. J.; Detweiler, Corrella S.

doi:10.1128/mbio.01801-21

Cited by 26 publications

(26 citation statements)

References 82 publications

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“…We therefore established whether treatment with D66 potentiates growth inhibition with novobiocin, an antibiotic that cannot traverse the outer membrane [ 26 ]. Control compounds included PMB and JD1, which permeabilizes inner membranes and is not expected to potentiate novobiocin [ 19 , 30 ] (Fig 2C and 2D ). D66 did not potentiate novobiocin at concentrations up to 150 μM ( Fig 2E ).…”

Section: Resultsmentioning

confidence: 99%

A small molecule that disrupts S. Typhimurium membrane voltage without cell lysis reduces bacterial colonization of mice

et al. 2022

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As pathogenic bacteria become increasingly resistant to antibiotics, antimicrobials with mechanisms of action distinct from current clinical antibiotics are needed. Gram-negative bacteria pose a particular problem because they defend themselves against chemicals with a minimally permeable outer membrane and with efflux pumps. During infection, innate immune defense molecules increase bacterial vulnerability to chemicals by permeabilizing the outer membrane and occupying efflux pumps. Therefore, screens for compounds that reduce bacterial colonization of mammalian cells have the potential to reveal unexplored therapeutic avenues. Here we describe a new small molecule, D66, that prevents the survival of a human Gram-negative pathogen in macrophages. D66 inhibits bacterial growth under conditions wherein the bacterial outer membrane or efflux pumps are compromised, but not in standard microbiological media. The compound disrupts voltage across the bacterial inner membrane at concentrations that do not permeabilize the inner membrane or lyse cells. Selection for bacterial clones resistant to D66 activity suggested that outer membrane integrity and efflux are the two major bacterial defense mechanisms against this compound. Treatment of mammalian cells with D66 does not permeabilize the mammalian cell membrane but does cause stress, as revealed by hyperpolarization of mitochondrial membranes. Nevertheless, the compound is tolerated in mice and reduces bacterial tissue load. These data suggest that the inner membrane could be a viable target for anti-Gram-negative antimicrobials, and that disruption of bacterial membrane voltage without lysis is sufficient to enable clearance from the host.

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Section: Resultsmentioning

confidence: 99%

A small molecule that disrupts S. Typhimurium membrane voltage without cell lysis reduces bacterial colonization of mice

et al. 2022

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“…Biocides act against multiple cellular targets and may promote the death of persister cells (in particular, dormant cells) since their antimicrobial activity is independent of the metabolic state [16,17]. However, several protective factors within the biofilm structure keep the persister cells away from the biocide action.…”

Section: Persister Biofilm Cells After Biocide Treatmentmentioning

confidence: 99%

“…However, the antimicrobial activity of biocides is multi-target and usually independent from the bacterial metabolic state. Biocides may promote the death of dormant bacterial cells [16,17]. Thus, persister cells from biocide treatment may not include that dormant population, critical for antibiotic therapy.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Susceptibility of Persister Biofilm Cells of Bacillus cereus and Pseudomonas fluorescens

et al. 2022

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The present study evaluates the antimicrobial susceptibility of persister cells of Bacillus cereus and Pseudomonas fluorescens after their regrowth in suspension and as biofilms. Two conventional (benzalkonium chloride—BAC and peracetic acid—PAA) and two emerging biocides (glycolic acid—GA and glyoxal—GO) were selected for this study. Persister cells resulted from biofilms subjected to a critical treatment using the selected biocides. All biocide treatments developed B. cereus persister cells, except PAA that effectively reduced the levels of vegetative cells and endospores. P. fluorescens persister cells comprise viable and viable but non-culturable cells. Afterwards, persister cells were regrown in suspension and in biofilms and were subjected to a second biocide treatment. In general, planktonic cultures of regrown persister cells in suspension lost their antimicrobial tolerance, for both bacteria. Regrown biofilms of persister cells had antimicrobial susceptibility close to those regrown biofilms of biocide-untreated cells, except for regrown biofilms of persister P. fluorescens after BAC treatment, which demonstrated increased antimicrobial tolerance. The most active biocide against persister cells was PAA, which did not promote changes in susceptibility after their regrowth. In conclusion, persister cells are ubiquitous within biofilms and survive after critical biocide treatment. The descendant planktonic and biofilms populations showed similar properties as the original ones.

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“…Cells can compensate for the dissipation of one component by enhancing the other to maintain the necessary level of PMF 29 . A number of chemicals disrupt PMF of S. aureus by dissipating either ΔΨ or ΔpH [30][31][32] . Halicin is a potential broad-spectrum antibacterial molecule that selectively dissipates ΔpH 31 .…”

Section: Introductionmentioning

confidence: 99%

“…Halicin is a potential broad-spectrum antibacterial molecule that selectively dissipates ΔpH 31 . The small molecule JD1 disrupts ΔΨ, kills MRSA cells, and significantly reduces biofilm formation 32 . Bedaquiline, SQ109, pyrazinamide, clofazimine, nitazoxanide, and 2-aminoimidazoles are also potent PMF inhibitors in gram-positive bacteria 30,33 .…”

Section: Introductionmentioning

confidence: 99%

PROTON MOTIVE FORCE INHIBITORS ARE DETRIMENTAL TO METHICILLIN-RESISTANTSTAPHYLOCOCCUS AUREUSPERSISTER CELLS

Mohiuddin

Ghosh

Kavousi

et al. 2022

Preprint

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Methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to conventional antibiotics. These pathogens can form persister cells, which are transiently tolerant to bactericidal antibiotics, making them extremely dangerous. Previous studies have shown the effectiveness of proton motive force (PMF) inhibitors at killing bacterial cells; however, whether these agents can launch a new treatment strategy to eliminate persister cells mandates further investigation. Here, using known PMF inhibitors and two different MRSA isolates, we showed that antipersister potency of PMF inhibitors seemed to correlate with their ability to disrupt PMF and permeabilize cell membranes. By screening a small chemical library to verify this correlation, we identified a subset of chemicals (including nordihydroguaiaretic acid, gossypol, trifluoperazine, and amitriptyline) that strongly disrupted PMF in MRSA cells by dissipating either the transmembrane electric potential (ΔΨ) or the proton gradient (ΔpH). These drugs robustly permeabilized cell membranes and reduced persister levels below the limit of detection. Overall, our study further highlights the importance of cellular PMF as a target for designing new antipersister therapeutics.

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Staphylococcal Bacterial Persister Cells, Biofilms, and Intracellular Infection Are Disrupted by JD1, a Membrane-Damaging Small Molecule

Cited by 26 publications

References 82 publications

A small molecule that disrupts S. Typhimurium membrane voltage without cell lysis reduces bacterial colonization of mice

A small molecule that disrupts S. Typhimurium membrane voltage without cell lysis reduces bacterial colonization of mice

Antimicrobial Susceptibility of Persister Biofilm Cells of Bacillus cereus and Pseudomonas fluorescens

PROTON MOTIVE FORCE INHIBITORS ARE DETRIMENTAL TO METHICILLIN-RESISTANTSTAPHYLOCOCCUS AUREUSPERSISTER CELLS

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