New Life for an Old Drug: the Anthelmintic Drug Niclosamide Inhibits Pseudomonas aeruginosa Quorum Sensing

Abstract

The need for novel antibacterial strategies and the awareness of the importance of quorum sensing (QS) in bacterial infections have stimulated research aimed at identifying QS inhibitors (QSIs). However, clinical application of QSIs identified so far is still distant, likely due to their unsuitability for use in humans. A promising way to overcome this problem is searching for anti-QS side activity among the thousands of drugs approved for clinical use in the treatment of different diseases. Here, we applied this strategy to the search for QSIs, by screening a library of FDA-approved compounds for their ability to inhibit the QS response in the Gram-negative pathogen Pseudomonas aeruginosa. We found that the anthelmintic drug niclosamide strongly inhibits the P. aeruginosa QS response and production of acyl-homoserine lactone QS signal molecules. Microarray analysis showed that niclosamide affects the transcription of about 250 genes, with a high degree of target specificity toward the QS-dependent regulon. Phenotypic assays demonstrated that niclosamide suppresses surface motility and production of the secreted virulence factors elastase, pyocyanin, and rhamnolipids, and it reduces biofilm formation. In accordance with the strong antivirulence activity disclosed in vitro, niclosamide prevented P. aeruginosa pathogenicity in an insect model of acute infection. Besides the finding that an FDA-approved drug has a promising antivirulence activity against one of the most antibiotic-resistant bacterial pathogens, this work provides a proof of concept that a lateral anti-QS activity can be detected among drugs already used in humans, validating a new approach to identify QSIs that could easily move into clinical applications.

Antiinfectives targeting enzymes and the proton motive force

“…By way of some examples, we show in Fig. 4 the structures of six prenyl synthase drug targets, together with known enzyme inhibitors that are also uncouplers [several of which are FDA-approved drugs (4,36) or are in clinical trials (2)]. All six proteins have polar-nonpolar active-site pockets that correlate with the involvement of charged-hydrophobic substrates/products or transition state/reactive intermediates, as shown in Fig.…”

“…In addition, nitazoxanide (13) has been found to kill both replicating and nonreplicating M. tuberculosis (30)(31)(32)(33), and Nathan and coworkers (30,31) were unable to develop resistant colonies using up to 10 12 cfu, proposing a dual "PMF + unknown target" mechanism of action. Niclosamide (12) has been proposed as a lead for the treatment of type II diabetes (34), and it is also an inhibitor of breast cancer stem-like cells (35) and an inhibitor of Pseudomonas aeruginosa quorum sensing (36). There has also been very recent interest in the development of DNP analogs such as DNP methyl ether (37), for treating diabetes, and of controlledrelease DNP formulations (38) as mild hepatic mitochondrial uncouplers for treating hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes.…”

Glyceryl trinitrate is a novel inhibitor of quorum sensing in <i>Pseudomonas aeruginosa</i>

“…This rationale has been used in previous studies. As a result, a number of useful quorum sensing inhibitors have been found among FDA approved drugs such as niclosamide, aspirin and diclofenac sodium [26][27][28] .…”

Niclosamide methanol solvate and niclosamide hydrate: structure, solvent inclusion mode and implications for properties

“…(Sanphui et al, 2012, Weinbach & Garbus, 1969 Very recently, it has also been investigated for additional therapeutic applications, including anti-bacterial and anti-tumor activities. (Helfman, 2011, Imperi et al, 2013, Yo et al, 2012 NCL is a BCS class II drug, virtually insoluble in water, and is 2 formulated as a suspension and in chewable tablet form. Although both NCL anhydrate and monohydrate are available for drug formulation, each has drawbacks; the high affinity of the anhydrate for water and the poorer solubility of the hydrate can cause sedimentation during storage.…”