Abstract
Combinations of more than two drugs are routinely used for the treatment of pathogens and tumors. High-order combinations may be chosen due to their non-overlapping resistance mechanisms or for favorable drug interactions. Synergistic/antagonistic interactions occur when the combination has a higher/lower effect than the sum of individual drug effects. The standard treatment of Mycobacterium tuberculosis (Mtb) is an additive cocktail of three drugs which have different targets. Herein, we experimentally measured all 190 pairwise interactions among 20 antibiotics against Mtb growth. We used the pairwise interaction data to rank all possible high-order combinations by strength of synergy/antagonism. We used drug interaction profile correlation as a proxy for drug similarity to establish exclusion criteria for ideal combination therapies. Using this ranking and exclusion design (R/ED) framework, we modeled ways to improve the standard 3-drug combination with the addition of new drugs. We applied this framework to find the best 4-drug combinations against drug-resistant Mtb by adding new exclusion criteria to R/ED. Finally, we modeled alternating 2-order combinations as a cycling treatment and found optimized regimens significantly reduced the overall effective dose. R/ED provides an adaptable framework for the design of high-order drug combinations against any pathogen or tumor.
Highlights
Combinations of more than two drugs are routinely used for the treatment of pathogens and tumors
Developed methods to measure high-order drug interactions showed that the standard treatments for Mycobacterium tuberculosis (Mtb) and B cell lymphoma (EIR and R-CHOP) were not synergistic[1,21]
We find that a minor change in the best 4-order combination, replacing inh with sq[1], results in the best 4-order combination against inh-resistant Mtb (Fig. 5c)
Summary
Combinations of more than two drugs are routinely used for the treatment of pathogens and tumors. Www.nature.com/scientificreports name bedaquline chloramphenicol clofazimine cycloserine ethambutol ethionamide fusidic acid imipenem isoniazid lassomycin linezolid moxifloxacin nitrofurantoin pentamidine pretomanid prothionamide rifampicin SQ109 tunicamycin vancomycin abbreviation bdq chl clz cys eth eta fus imp inh las lin mox nit pen pre pro rif sq[1] tun van Recently developed methods to measure high-order drug interactions showed that the standard treatments for Mtb and B cell lymphoma (EIR and R-CHOP) were not synergistic[1,21]. Our ranking/exclusion design (R/ED) framework proposes a pipeline for nominating best high-order combinations and provides several test cases for treatment of drug-resistant Mtb
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
