Abstract
We recently described the novel anti-persister compound 1-[(2,4-dichlorophenethyl)amino]-3-phenoxypropan-2-ol (SPI009), capable of directly killing persister cells of the Gram-negative pathogen Pseudomonas aeruginosa. This compound also shows antibacterial effects against non-persister cells, suggesting that SPI009 could be used as an adjuvant for antibacterial combination therapy. Here, we demonstrate the broad-spectrum activity of SPI009, combined with different classes of antibiotics, against the clinically relevant ESKAPE pathogens Enterobacter aerogenes, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa, Enterococcus faecium and Burkholderia cenocepacia and Escherichia coli. Importantly, SPI009 re-enabled killing of antibiotic-resistant strains and effectively lowered the required antibiotic concentrations. The clinical potential was further confirmed in biofilm models of P. aeruginosa and S. aureus where SPI009 exhibited effective biofilm inhibition and eradication. Caenorhabditis elegans infected with P. aeruginosa also showed a significant improvement in survival when SPI009 was added to conventional antibiotic treatment. Overall, we demonstrate that SPI009, initially discovered as an anti-persister molecule in P. aeruginosa, possesses broad-spectrum activity and is highly suitable for the development of antibacterial combination therapies in the fight against chronic infections.
Highlights
MATERIALS AND METHODSAntibiotic resistance is rapidly increasing in the majority of nosocomial pathogens, complicating the effective treatment of bacterial infections and transforming once cured diseases into serious human health threats (European Centre for Disease Prevention and Control, 2013; O’Neill, 2016)
The activity of SPI009 was previously assessed in P. aeruginosa PA14 and several clinical isolates where combination with ofloxacin significantly decreased the persister fraction in all strains tested (Liebens et al, 2017)
Combination of the antibiotic with 17 μg/mL SPI009 significantly decreased the number of surviving bacteria for five of the eight species with reductions in CFU ranging between 1.5 ± 0.1 and 6.0 ± 0.2 log units and complete eradication of K. pneumoniae
Summary
MATERIALS AND METHODSAntibiotic resistance is rapidly increasing in the majority of nosocomial pathogens, complicating the effective treatment of bacterial infections and transforming once cured diseases into serious human health threats (European Centre for Disease Prevention and Control, 2013; O’Neill, 2016). In an attempt to guide research and development toward the most critical pathogens, the World Health Organization (WHO) recently published their ‘global priority list,’ containing 12 bacterial pathogens that raise particular concern (WHO, 2017) Among these are the so-called ESKAPE pathogens, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa, and Enterobacter spp., which efficiently evade antibiotic treatment and represent new paradigms in pathogenesis, transmission, and resistance (Rice, 2008). Together, this select group of bacteria is responsible for most of the hospital-acquired infections and, despite increasing research efforts, therapeutic options remain scarce (Bassetti et al, 2013; Pendleton et al, 2013). Effective elimination of persister cells could significantly improve patient outcomes, but their small numbers and the apparent redundancy in persister mechanisms greatly hampers the development of targeted anti-persister therapies
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