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Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently.sup.1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner. An analysis of the interactions between 15 drugs and 25 gut bacterial strains shows that bioaccumulation of drugs within bacterial cells is another mechanism through which gut microorganisms can alter drug availability and efficacy., Author(s): Martina Klünemann [sup.1] [sup.9] , Sergej Andrejev [sup.1] [sup.10] , Sonja Blasche [sup.1] [sup.2] , Andre Mateus [sup.1] , Prasad Phapale [sup.1] , Saravanan Devendran [sup.1] , Johanna Vappiani [...]

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.sup.1,2. 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.Screening pairwise combinations of antibiotics and other drugs against three bacterial pathogens reveals that antagonistic and synergistic drug-drug interactions are specific to microbial species and strains., Author(s): Ana Rita Brochado [sup.1] , Anja Telzerow [sup.1] , Jacob Bobonis [sup.1] , Manuel Banzhaf [sup.1] [sup.11] , André Mateus [sup.1] , Joel Selkrig [sup.1] , Emily Huth [sup.2] [...]

Advances in our ability to systematically introduce and track controlled genetic variance in microorganisms have, in the past decade, fuelled high-throughput reverse genetics approaches. When coupled to quantitative readouts, such approaches are extremely powerful at elucidating gene function and providing insights into the underlying pathways and the overall cellular network organization. Yet, until now, all efforts to quantify microbial macroscopic phenotypes have been restricted to monitoring growth in a small number of model microorganisms. We have developed an image analysis software named Iris, which allows for systematic exploration of a number of orthogonal-to-growth processes, including biofilm formation, colony morphogenesis, envelope biogenesis, sporulation and reporter activity. In addition, Iris provides more sensitive growth measurements than currently available software and is compatible with a variety of different microorganisms, as well as with endpoint or kinetic data. We used Iris to reanalyse existing chemical genomics data in Escherichia coli and to perform proof-of-principle screens on colony biofilm formation and morphogenesis of different bacterial species and the pathogenic fungus Candida albicans. We thereby recapitulated existing knowledge but also identified a plethora of additional genes and pathways involved in both processes.