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. 2019 Aug 15;9:11876. doi: 10.1038/s41598-019-48410-y

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Improving the current M. tuberculosis treatment by adding new drugs. (a) At the top, static interactions of eth, inh and rif (EIR) with the other 17 drugs are shown. Green vertical rectangles indicate drugs that are similar with a member of EIR. inh is similar to bdq and eta, rif is similar to van. Therefore, bdq, eta and van are excluded from further consideration. The estimated static interaction score for each 4-order combination is ranked and shown in black-white. Pre and clz rank high among 4-order combinations that include EIR. At the bottom, lytic interactions for EIR with other 17 drugs are shown. Unknown interactions are shown in orange. The estimated lytic interaction score for each 4-order combination is ranked and shown in black-white. Clz ranks high in lytic synergy, however pre ranks low due to its antagonistic lytic interaction with eth. Therefore, clz emerges as the top ranked compound to complement EIR. (b) Relationship between combination order and rank% among all combinations including EIR. %rank for all combinations in each combination order is shown as a scatter plot jittered in y axis. The combination with best %rank in each order is indicated with a circle, with its color corresponding to its %rank among all possible combinations. EIR is the only 3-order combination and ranks at 6%. Addition of clz greatly improves the static and lytic synergy ranks of EIR, and 4-order combination EIR + clz is ranked at 0.01%. A 6-order combination involving EIR + clz + fus + sq1 ranks in the first 0.1%.