Enterococcus faecalis Modulates Immune Activation and Slows Healing During Wound Infection

Chong, Kelvin Kian Long; Tay, Wei Hong; Janela, Baptiste; Yong, Adeline Mei Hui; Liew, Tze Horng; Madden, Leigh; Keogh, Damien; Barkham, Timothy; Ginhoux, Florent; Becker, David L.; Kline, Kimberly

doi:10.1093/infdis/jix541

Cited by 95 publications

(127 citation statements)

References 48 publications

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“…Similar growth-driven changes in pH (in antibioticfree environments) have been shown to modulate intercellular interactions (59) and even promote ecological suicide in other microbial species (60). In addition to these in vitro studies, recent work shows that E. faecalis infections started from high-and low-dose inocula lead to different levels of immune response and colonization in a mouse model (61). If similar feedback loops between population density and growth Growth rate is estimated, as in (11), from the average media flow rate required to maintain populations at the specified density in the presence of a constant drug concentration of 0.5 µg/mL.…”

Section: Introductionmentioning

confidence: 90%

Delayed antibiotic exposure induces population collapse in enterococcal communities with drug-resistant subpopulations

Hallinen

Karslake

Wood

2019

Preprint

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Bacteria exploit a diverse set of defenses to survive exposure to antibiotics.While the molecular and genetic underpinnings of antibiotic resistance are increasingly understood, less is known about how these molecular events influence microbial dynamics on the population scale. In this work, we show that the dynamics of E. faecalis communities exposed to antibiotics can be surprisingly rich, revealing scenarios where-for example-increasing population size or delaying drug exposure can promote population collapse. Specifically, we combine experiments in computer-controlled bioreactors with simple mathematical models to reveal density-dependent feedback loops that couple population growth and antibiotic efficacy when communities include drug-resistant (β-lactamase producing) subpopulations. The resulting communities exhibit a wide range of behavior, including population survival, population collapse, or one of two qualitatively distinct bistable behaviors where survival is favored in either small or large populations. These dynamics reflect competing density-dependent effects of different subpopulations, with growth of drug-sensitive cells increasing but growth of drug-resistant cells decreasing effective drug inhibition. Guided by these results, we experimentally demonstrate how populations receiving immediate drug influx may sometimes thrive, while identical populations exposed to delayed drug influx (and lower average drug concentrations) collapse. These results illustrate that the spread of drug resistant determinants-even in a simplified single-species communities-may be governed by potentially counterintuitive dynamics driven by population-level interactions.

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Section: Introductionmentioning

confidence: 90%

Delayed antibiotic exposure induces population collapse in enterococcal communities with drug-resistant subpopulations

Hallinen

Karslake

Wood

2019

Preprint

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“…E. faecalis is the most common strain of bacteria that is isolated in wounds such as burns, diabetic foot ulcers, and surgical sites. It is responsible for infections which are challenging to treat because of its intrinsic and acquired resistance to a wide class of antibiotics . Bacterial biofilms are a major factor that impedes wound healing.…”

Section: Resultsmentioning

confidence: 99%

“…Its resistance to many antibiotics is due to factors such as biofilm formation; its capability to use serum in the blood as a source of nutrition in a long period of time when there is lack of nutritional source; penicillin binding proteins make it naturally resistant to penicillin and as such, penicillin inhibits the bacteria activity but does not destroy the bacteria and it can absorb folic acid making the antibiotics ineffective . E. faecalis in wound contribute to delayed re‐epithelisation and wound healing . Wound dressings A and B were effective against E. faecalis when compared to the STM and NLD.…”

Section: Resultsmentioning

confidence: 99%

Development, characterization, and in vitro evaluation of water soluble poloxamer/pluronic‐mastic gum‐gum acacia‐based wound dressing

Buyana

Aderibigbe

Ray

et al. 2019

J of Applied Polymer Sci

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Bacterial infections are serious complications associated with wounds. Wounds can become chronic due to bacterial infections. In this research, lyophilized wound dressings were prepared from poloxamer, pluronic, mastic gum, and gum acacia. The wound dressings were loaded with metal‐based nanoparticles and carbon‐based materials. They exhibited effective antibacterial activity, water‐soluble, biodegradable with the capability to absorb large amounts of wound exudates. The bandages were analyzed using Fourier transform infrared spectroscopy, scanning electron microscopy/energy‐dispersive X‐ray spectroscopy, thermogravimetric analysis, and transmission electron microscopy followed by porosity and water uptake. TEM confirmed the successful incorporation of the metal‐based NPs and carbon‐based materials into the wound dressings. The TGA confirmed that the wound dressings are thermally stable. The wound dressings were also characterized by a high uptake of water to form a gel which was soluble in water indicating their useful application for wounds with large wound exudate, sensitive and damaged skin. The unique properties of the wound dressings indicate that they are potential materials for the treatment of chronic wounds in patients with sensitive skin. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48728.

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“…The murine wound infection model was carried as described with minor modifications (18). Briefly, we grew the bacterial strains in 15 mL Tryptic Soy Broth supplemented with 0.25% glucose for 16-18 hours, at 37°C with continuous shaking at 200 rpm.…”

Section: Methodsmentioning

confidence: 99%

Combined efficacy of a novel antimicrobial cationic peptide polymer with conventional antibiotics to combat multi-drug resistant pathogens

Thappeta

Vikhe

Yong

et al. 2019

Preprint

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13Antibiotic-resistant infections are predicted to kill 10 million people worldwide per year 14 by 2050 and to cost the global economy 100 trillion USD. Novel approaches and 15 alternatives to conventional antibiotics are urgently required to combat antimicrobial 16 resistance. We have synthesized a chitosan-based oligolysine antimicrobial peptide, 17 CSM5-K5, which targets multidrug resistant (MDR) bacterial species. Here we show 18 that CSM5-K5 exhibits rapid bactericidal activity against methicillin resistant 19 Staphylococcus aureus (MRSA), MDR Escherichia coli, and vancomycin resistant 20 Enterococcus faecalis (VRE). Combinatorial therapy of CSM5-K5 with antibiotics to 21 which each organism is otherwise resistant restores sensitivity to the conventional 22 antibiotic. CSM5-K5 alone significantly reduced pre-formed bacterial biofilm by two-four 23 orders of magnitude and, in combination with traditional antibiotics, reduced pre-formed 24 biofilm by more than two-three orders of magnitude at sub inhibitory concentrations. 25Moreover, using a mouse excisional wound infection model, CSM5-K5 treatment 26 reduced bacterial burdens by one to three orders of magnitude, and acted 27 synergistically with vancomycin and tetracycline to clear VRE and MDR E. coli, 28 respectively. Importantly, little to no resistance against CSM5-K5 arose for any of the 29 three MDR bacteria during 15 days of serial passage. This work demonstrates the 30 feasibility and benefits of using this synthetic cationic peptide as alternative to, or in 31 combination with, traditional antibiotics to treat infections caused by MDR bacteria. 32 33Antibiotic resistance is a threat to global public health and sustainability (1). Antibiotic 35 resistance currently accounts for an estimated 70,000 annual deaths globally, and in the 36 absence of new therapeutics, infections caused by resistant "superbugs" could kill an 37 additional 10 million people each year worldwide by 2050, surpassing cancer (2). 38 Moreover, by 2050, antibiotic resistant infections are estimated to cost up to 3.5% of the 39 global GDP, equivalent to 100 trillion USD (2). Because corporate antibiotic 40 development pipelines of have progressively declined over the past 20 years (3), there 41 is substantial interest in seeking alternative therapeutic approaches to combat these 42 multidrug resistant (MDR) pathogens. 43 44 Host-derived antimicrobial peptides (CAMPs), typically composed of cationic and 45 hydrophobic domains, have garnered interest as alternative therapies for MDR 46 infections. CAMPs are electrostatically attracted to anionic bacterial cell surfaces, 47followed by peptide insertion into the lipid bilayer via their hydrophobic residues (4, 5). 48Chitosan is a polysaccharide composed of repeating N-glucosamine, with a structure 49 similar to that of bacterial peptidoglycan. This unique feature of chitosan renders it 50 potentially compatible with the bacterial cell wall. Numerous studies have examined the 51 efficacy of chitosan-CAMP hybrids containing quaterna...

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Enterococcus faecalis Modulates Immune Activation and Slows Healing During Wound Infection

Abstract: Enterococcus faecalis wound infections remain poorly understood. We demonstrate in vivo that E faecalis infection results in 2 different states: colonization or infection. We show that E faecalis infection modulates host immunity, resulting in persistent infection and delayed healing.

Cited by 95 publications

References 48 publications

Delayed antibiotic exposure induces population collapse in enterococcal communities with drug-resistant subpopulations

Delayed antibiotic exposure induces population collapse in enterococcal communities with drug-resistant subpopulations

Development, characterization, and in vitro evaluation of water soluble poloxamer/pluronic‐mastic gum‐gum acacia‐based wound dressing

Combined efficacy of a novel antimicrobial cationic peptide polymer with conventional antibiotics to combat multi-drug resistant pathogens

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