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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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Exploring best 4-order combinations and 2-order drug cycling options against drug-resistant M. tuberculosis. In each panel, all pairwise static λ and lytic λ scores among four drugs are given as heatmaps. (top) Heatmaps correspond to best 4-order combinations against drug sensitive or resistant M. tuberculosis. The scores above heatmaps indicate the estimated 4-order interaction scores. (a) eta + fus + pre + van is the lowest ranked 4-order combination in our framework. (b) Since rif and van are similar drugs, we cannot use van against a rif-resistant Mtb strain. Therefore, the lowest ranked 4-order combination shown in (a) is not applicable. When rif and van are excluded, the lowest ranking 4-order combination is clz + fus + inh + sq1. (c) Similarly, since inh and eta are similar drugs, we cannot use eta against an inh-resistant Mtb strain. The best 4-order combination against inh-resistant strain is found as fus + pre + sq1 + van. (d,e) The best 4-order combinations against Mtb strains resistant to rif-inh or rif-inh-mox. (f) The best 4-order combination that includes current Mtb treatment. (bottom) Magenta and green frames show the 2-order combinations nominated for cycling. The two scores correspond to measured static λ and lytic λ scores for each pairwise combination. (g) Best 2-order combination cycling is pre + van and bdq + clz. (h–k) Best 2-order cycling options for Mtb strains resistant to indicated drugs. (l) When considered as two 2-order combinations, EIR + clz is split into clz + inh and eth + rif. For each resistance scenario and EIR + clz, the static λ and lytic λ scores in cycling is superior to 4-order combinations.