Abstract
Drug resistance in bacterial infections and cancers constitutes a major threat to human health. Treatments often include several interacting drugs, but even potent therapies can become ineffective in resistant mutants. Here, we simplify the picture of drug resistance by identifying scaling laws that unify the multidrug responses of drug-sensitive and -resistant cells. On the basis of these scaling relationships, we are able to infer the two-drug response of resistant mutants in previously unsampled regions of dosage space in clinically relevant microbes such as E.coli, E.faecalis, S.aureus, and S.cerevisiae as well as human non-small-cell lung cancer, melanoma, and breast cancer stem cells. Importantly, we find that scaling relations also apply across evolutionarily close strains. Finally, scaling allows one to rapidly identify new drug combinations and predict potent dosage regimes for targeting resistant mutants without any prior mechanistic knowledge about the specific resistance mechanism.
Highlights
Treatment strategies for infectious diseases and cancers often involve multiple drugs that must be combined, adapted, and refined to target evolving cell populations
A similar decrease in the interactions between antibiotics occurs in vancomycin-resistant E. faecalis (Palmer et al, 2011), where the synergy (Rand and Houck, 2004) in the combination of daptomycin and ampicillin is reduced in certain daptomycin-resistant mutants (Figure 1D)
In E. coli exposed to the weakly synergistic combination of doxycycline and erythromycin, the drug pair becomes increasingly synergistic in some multi-drug resistant mutants (Figure 1E)
Summary
Introduction Treatment strategies for infectious diseases and cancers often involve multiple drugs that must be combined, adapted, and refined to target evolving cell populations. We postulate that the effect of resistance can be: (i) to rescale the concentration of each drug, with the scaling factors a1or a2 specific to each mutant, and/or (ii) to change the interaction between drugs by rescaling the amplitude of the 2-drug toxicity function C(D1) (Equation 2) by a single parameter, a3 (Figure 3).
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