Standardized RS Ratio Metrics To Assess Tuberculosis Antimicrobial Efficacy and Potency

Abstract

The sigmoid E_max model was used to describe the rRNA synthesis ratio (RS ratio) response of Mycobacterium tuberculosis to antimicrobial concentration. RS-E_max measures the maximal ability of a drug to inhibit the RS ratio and can be used to rank-order drugs based on their RS ratio effect. RS-EC₉₀ is the concentration needed to achieve 90% of the RS-E_max, which may guide dose selection to achieve a maximal RS ratio effect in vivo.

Keywords: Mycobacterium tuberculosis; RS ratio; antibiotic; antimicrobial; drug effects; drug therapy; precursor rRNA.

FIG 1

RS ratio concentration response sigmoid E_max models and correlations with conventional metrics. (A) The percent effect on the RS ratio was defined as the percent decrease in the RS ratio after 48 h of drug exposure, compared to the pre-drug exposure value. The percent effect was plotted as a function of the log-transformed concentrations of the drug, as described by the equation: Y = E_min + (E_max − E_min) / (1 + 10^{log[EC50]−X}· Hill slope), with Y indicating the percent effect and X indicating the log-transformed concentration. All of the dose response curves were generated, and all of the data were analyzed, using GraphPad Prism 9. Curves were fit to the observed data using least-squares regression and medium convergence criteria (maximum iterations = 1,000). No y axis weighting or outlier exclusion filters were applied. The best-fit and range values (defined as 95% confidence intervals) for the RS-E_max, RS-E_min, RS-EC₅₀, and Hill slopes are listed in Table 1 for each drug. Unstable parameters for which a 95% confidence interval could not be determined are indicated. The best-fit curves are depicted with a solid black line. Additional dashed lines depict the RS-E_max (green horizontal), mean control RS ratio response at 48 h (gray horizontal), and RS-EC₉₀ (yellow vertical). (B) The correlations between the standard MIC (circles) or MIC_extr (triangles) with RS-EC₉₀. (C) The correlation between the ΔCFU-E_max and RS-E_max. Linezolid was not included in the correlations due to its inverse effect on the RS ratio.