Species-specific activity of antibacterial drug combinations

Abstract

The spread of antimicrobial resistance has become a serious public health concern, making once-treatable diseases deadly again and undermining the achievements of modern medicine. Drug combinations can help to fight multi-drug-resistant bacterial infections, yet they are largely unexplored and rarely used in clinics. Here we profile almost 3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in six strains from three Gram-negative pathogens-Escherichia coli, Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa-to identify general principles for antibacterial drug combinations and understand their potential. Despite the phylogenetic relatedness of the three species, more than 70% of the drug-drug interactions that we detected are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies. Overall, antagonisms are more common than synergies and occur almost exclusively between drugs that target different cellular processes, whereas synergies are more conserved and are enriched in drugs that target the same process. We provide mechanistic insights into this dichotomy and further dissect the interactions of the food additive vanillin. Finally, we demonstrate that several synergies are effective against multi-drug-resistant clinical isolates in vitro and during infections of the larvae of the greater wax moth Galleria mellonella, with one reverting resistance to the last-resort antibiotic colistin.

Bacterial defenses against a natural antibiotic promote collateral resilience to clinical antibiotics

“…due to structural similarities like those shared by PYO and fluoroquinolones. This inference is supported by recent evidence that certain food additives or synthetic drugs antagonize the efficacy of specific clinical antibiotics by triggering stress responses in cells, including the induction of efflux pumps 55 . In fact, bacterially-produced toxic metabolites that promote antibiotic tolerance and resistance in human pathogens need not be limited to the types of molecules traditionally thought of as natural antibiotics.…”

Pyphe: A python toolbox for assessing microbial growth and cell viability in high-throughput colony screens

“…The availability of knock-out libraries has revolutionised forward genetics (Giaever and Nislow, 2014), and large collections of wild isolates (Jeffares et al, 2015;Peter et al, 2018) as well as synthetic populations (Bloom et al, 2013;Cubillos et al, 2013) have proven a powerful tool to study complex traits. More recently, high-throughput phenomics, the systematic measurement of fitness for hundreds of conditions and/or hundreds/thousands of strains in parallel, is driving our systems-level understanding of gene function (Brochado et al, 2018;Costanzo et al, 2016;Kuzmin et al, 2018;Nichols et al, 2011).…”

Constructing and deconstructing the bacterial cell wall

“…These paths include a renewed focus in antibacterial natural-product discovery, 14,[42][43][44][45][46][47][48] the identification of new targets, [49][50][51][52] the exploitation of the nutritional needs of the bacteria for the facilitated delivery of antibiotic prodrugs and conjugates, [53][54][55] the creation of hybrid antibiotic structures, 56 understanding the intersection of primary metabolism and antibiotic mechanism, 57,58 and the discernment of effective combinations of antibiotics with other antibiotic, enhancer, or adjuvant structures. [59][60][61][62][63][64][65][66] This essay is a personal perspective, exemplified by the recent efforts of our laboratory, with respect to understanding the intimate relationship between the biochemistry of antibiotic resistance and antibiotic discovery. These efforts combine the paths of new structure, new mechanisms, renewed target evaluation, and the evaluation of antibiotic-adjuvant combinations that target the bacterial cell wall.…”