Synergistic Activity of Niclosamide in Combination With Colistin Against Colistin-Susceptible and Colistin-Resistant Acinetobacter baumannii and Klebsiella pneumoniae

Ayerbe-Algaba, Rafael; Gil-Marqués, María Luisa; Me, Jiménez-Mejías; Sánchez-Encinales, Viviana; Parra-Millán, Raquel; Pachón-Ibáñez, María Eugenia; Pachón, Jerónimo; Smani, Younes

doi:10.3389/fcimb.2018.00348

Cited by 59 publications

(48 citation statements)

References 40 publications

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“…Rajamuthiah et al [66] described the efficacy of niclosamide (a bacteriostatic agent included in the salicylanilides family) against methicillin-, vancomycin-, linezolid-or daptomycin-resistant S. aureus isolates, probably damaging the bacterial membrane. Niclosamide inhibited QS and virulence genes in P. aeruginosa [67], such as phospholipase C, LasA protease, pyocyanin, chitinase, rhamnolipids… It also increased the negative charges of the cell walls from A. baumannii and K. pneumoniae, which results in synergy with cationic colistin, resensitizing both pathogens against this antibiotic [68]. These summarized experiments show consistent results while they were performed using four different bacterial species and conditions.…”

Section: Anti-helmintic Drugssupporting

confidence: 62%

Strategies to Combat Persistent Infectious Diseases

Pacios¹,

Blasco²,

Bleriot³

et al. 2019

Preprint

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Antibiotic failure is one of the most worrying health problems worldwide. Nowadays we are facing an international crisis where several issues are involved: new antibiotics are not being discovered any longer, resistance mechanisms become spread in nearly every clinical isolate of bacteria and the appearance of recurrent infections caused by persistent bacteria complicates the overcoming of infections. In this context, it has been explored new anti-infectious strategies against MDR and persistent bacteria as well as the rescue of FDA-approved compounds (drug repurposing). Among the highlighted new anti-infectious strategies we find anti-microbial peptides, anti-virulence compounds, phage therapy and new molecules. On the other hand, as drugs of repurposing that have been described, we have anti-inflammatory compounds, anti-psychotics, anti-helmintic drugs, anti-cancerous and statins.

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Section: Anti-helmintic Drugssupporting

confidence: 62%

Strategies to Combat Persistent Infectious Diseases

Pacios¹,

Blasco²,

Bleriot³

et al. 2019

Preprint

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“…It was next reasoned that increased niclosamide influx via outer membrane permeabilization might mitigate TolC-mediated efflux. Therefore, membrane permeabilizing polymyxin antibiotics were investigated for synergy and, consistent with recent reports (29–31), synergy was observed when colistin or polymyxin B were co-administered with niclosamide (δ = 28.1 and 25.6, respectively) ( Fig. 3b-c ).…”

Section: Resultssupporting

confidence: 80%

“…In isolation, niclosamide exhibits no activity against most Gram-negative pathogens (1, 23). Nevertheless, it was recently reported that in vitro co-administration of niclosamide and colistin can overcome colistin-resistance in Gram-negative bacteria (29–31). While these findings suggest that niclosamide may hold cryptic antibiotic potential, the molecular basis that underlies its antibiotic mode of action, synergy, and the lack of efficacy against Gram-negative bacteria has been hitherto unknown.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic understanding enables the rational design of salicylanilide combination therapies for Gram-negative infections

Copp

Pletzer

Brown³

et al. 2020

Preprint

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21One avenue to combat multidrug-resistant Gram-negative bacteria is the co-administration 22 of multiple drugs (combination therapy), which can be particularly promising if drugs 23 synergize. The identification of synergistic drug combinations, however, is challenging. 24 Detailed understanding of antibiotic mechanisms can address this issue by facilitating the 25 rational design of improved combination therapies. Here, using diverse biochemical and 26 genetic assays, we reveal the molecular mechanisms of niclosamide, a clinically-approved 27 salicylanilide compound, and demonstrate its potential for Gram-negative combination 28 therapies. We discovered that Gram-negative bacteria possess two innate resistance 29 mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated 30 by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was 31 compromised, niclosamide became a potent antibiotic, dissipating the proton motive force 32 (PMF), increasing oxidative stress and reducing ATP production to cause cell death. These 33 insights guided the identification of diverse compounds that synergized with salicylanilides 34 when co-administered (efflux inhibitors, membrane permeabilizers, and antibiotics that are 35 expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may 36 have broad utility in combination therapies. We validate these findings in vivo using a 37 murine abscess model, where we show that niclosamide synergizes with the membrane 38 permeabilizing antibiotic colistin against high-density infections of multidrug-resistant 39 Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase 40 activity is a potential route to adaptive niclosamide resistance but show that this causes 41 collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how 42 mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can 43 rationally guide the discovery, development and stewardship of novel combination 44 therapies. 45 46 Importance 47There is a critical need for more effective treatments to combat multidrug-resistant Gram-48 negative infections. Combination therapies are a promising strategy, especially when these 49 enable existing clinical drugs to be repurposed as antibiotics. We reveal the mechanisms 50 of action and basis of innate Gram-negative resistance for the anthelmintic drug 51 niclosamide, and subsequently exploit this information to demonstrate that niclosamide 52 and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug 53 efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in 54 vitro against a diverse range of recalcitrant Gram-negative clinical isolates, and in vivo in 55 a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to 56 niclosamide, but show that evolution of these enzymes for enhanced niclosamide resistance 57 confers a collateral s...

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“…Niclosamide inhibits QS and virulence genes in P. aeruginosa [67], such as phospholipase C, LasA protease, pyocyanin, chitinase, and rhamnolipids. It also increases the negative charges on the cell walls of A. baumannii and K. pneumoniae, resulting in synergistic interaction with cationic colistin, resensitizing both pathogens to this antibiotic [68]. These studies show consistent results although they were performed with four different bacterial species and conditions.…”

Section: Anti-helminthic Drugssupporting

confidence: 55%

Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

et al. 2020

View full text Add to dashboard Cite

Antibiotic failure is one of the most worrying health problems worldwide. We are currently facing an international crisis with several problematic facets: new antibiotics are no longer being discovered, resistance mechanisms are occurring in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria are hampering the successful treatment of infections. In this context, new anti-infectious strategies against multidrug-resistant (MDR) and persistent bacteria, as well as the rescue of Food and Drug Administration (FDA)-approved compounds (drug repurposing), are being explored. Among the highlighted new anti-infectious strategies, in this review, we focus on antimicrobial peptides, anti-virulence compounds, phage therapy, and new molecules. As drugs that are being repurposed, we highlight anti-inflammatory compounds, anti-psychotics, anti-helminthics, anti-cancerous drugs, and statins.

show abstract

Synergistic Activity of Niclosamide in Combination With Colistin Against Colistin-Susceptible and Colistin-Resistant Acinetobacter baumannii and Klebsiella pneumoniae

Cited by 59 publications

References 40 publications

Strategies to Combat Persistent Infectious Diseases

Strategies to Combat Persistent Infectious Diseases

Mechanistic understanding enables the rational design of salicylanilide combination therapies for Gram-negative infections

Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

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