Abstract
Antibiotics are losing efficacy due to the rapid evolution and spread of resistance. Treatments targeting bacterial virulence factors have been considered as alternatives because they target virulence instead of pathogen viability, and should therefore exert weaker selection for resistance than conventional antibiotics. However, antivirulence treatments rarely clear infections, which compromises their clinical applications. Here, we explore the potential of combining antivirulence drugs with antibiotics against the opportunistic human pathogen Pseudomonas aeruginosa. We combined two antivirulence compounds (gallium, a siderophore quencher, and furanone C-30, a quorum sensing [QS] inhibitor) together with four clinically relevant antibiotics (ciprofloxacin, colistin, meropenem, tobramycin) in 9×9 drug concentration matrices. We found that drug-interaction patterns were concentration dependent, with promising levels of synergies occurring at intermediate drug concentrations for certain drug pairs. We then tested whether antivirulence compounds are potent adjuvants, especially when treating antibiotic resistant (AtbR) clones. We found that the addition of antivirulence compounds to antibiotics could restore growth inhibition for most AtbR clones, and even abrogate or reverse selection for resistance in five drug combination cases. Molecular analyses suggest that selection against resistant clones occurs when resistance mechanisms involve restoration of protein synthesis, but not when efflux pumps are up-regulated. Altogether, our work provides a first systematic analysis of antivirulence-antibiotic combinatorial treatments and suggests that such combinations have the potential to be both effective in treating infections and in limiting the spread of antibiotic resistance.
Highlights
We found that the dose-response curves for antibiotics followed sigmoid functions (Fig 1) characterized by (i) a low antibiotic concentration range that did not inhibit bacterial growth, (ii) an intermediate antibiotic concentration range that significantly reduced bacterial growth, and (iii) a high antibiotic concentration range that completely stalled bacterial growth
We systematically explored the effects of combining antibiotics with antivirulence compounds as a potentially promising strategy to fight susceptible and antibiotic resistant opportunistic human pathogens
While colistin and tobramycin primarily interacted synergistically with the antivirulence compounds, independent and antagonistic interactions occurred for ciprofloxacin and meropenem in combination with the antivirulence compounds (Figs 3 and 4)
Summary
Scientists together with the World Health Organization (WHO) forecast that the rapid evolution and spread of antibiotic resistant bacteria will lead to a worldwide medical crisis [1,2,3]. Novel innovative approaches that are both effective against pathogens and robust to the emergence and spread of resistance are urgently needed [6,7] One such approach involves the use of compounds that disarm rather than kill bacteria. While a few studies have already considered such combinatorial treatments [12,13,14,15,16,17,18], we currently have no comprehensive understanding of how different types of antibiotics and antivirulence drugs interact, whether interactions are predominantly synergistic or antagonistic, and how combinatorial treatments affect growth and the spread of antibiotic resistant strains Such knowledge is, essential if such therapies are supposed to make their way into the clinics, as drug interactions and their effects on antibiotic resistance evolution will determine both the efficacy and sustainability of treatments. We sequenced the genomes of the evolved AtbR clones to understand the genetic basis that might drive the observed effects on pathogen growth and selection for or against antibiotic resistance
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