A generalized growth law for translation- and transcription-targeting antibiotics captures drug interactions

Bacterial growth laws quantitatively connect intracellular resource allocation to growth rate, enabling accurate predictions of physiology and antibiotic responses. Yet these laws have been rigorously tested for only a handful of perturbations. Here, we show that the growth law linking ribosome levels to growth rate under translation-inhibiting antibiotics is not universal, but rather depends on the antibiotic's mechanism of action. Quantitative proteomics across finely resolved one- and two-dimensional antibiotic gradients showed that inhibitors of translocation elongation or peptide bond formation elicit the canonical rise in ribosome levels, consistent with the growth law. By contrast, antibiotics disrupting translation initiation or fidelity produced distinct responses without ribosome upregulation. The transcription inhibitor rifampicin even reduced ribosome abundance. Combining antibiotics with divergent ribosome responses revealed a generalized growth law, in which the individual responses to perturbations superimpose. Embedding this law in a mathematical model explains distinct drug interaction patterns observed between rifampicin and different translation inhibitors. A low-dimensional structure pervades the entire proteome, enabling prediction of responses to drug pairs based on single-drug measurements. Together, these findings broaden the scope of bacterial growth laws and provide new principles for predicting responses to antibiotic combinations.