1 research outputs found
Prediction of drug penetration in tuberculosis lesions
The
penetration of antibiotics in necrotic tuberculosis lesions is heterogeneous
and drug-specific, but the factors underlying such differential partitioning
are unknown. We hypothesized that drug binding to macromolecules in
necrotic foci (or caseum) prevents passive drug diffusion through
avascular caseum, a critical site of infection. Using a caseum binding
assay and MALDI mass spectrometry imaging of tuberculosis drugs, we
showed that binding to caseum inversely correlates with passive diffusion
into the necrotic core. We developed a high-throughput assay relying
on rapid equilibrium dialysis and a caseum surrogate designed to mimic
the composition of native caseum. A set of 279 compounds was profiled
in this assay to generate a large data set and explore the physicochemical
drivers of free diffusion into caseum. Principle component analysis
and modeling of the data set delivered an in silico signature predictive
of caseum binding, combining 69 molecular descriptors. Among the major
positive drivers of binding were high lipophilicity and poor solubility.
Determinants of molecular shape such as the number of rings, particularly
aromatic rings, number of sp<sup>2</sup> carbon counts, and volume-to-surface
ratio negatively correlated with the free fraction, indicating that
low-molecular-weight nonflat compounds are more likely to exhibit
low caseum binding properties and diffuse effectively through caseum.
To provide simple guidance in the property-based design of new compounds,
a rule of thumb was derived whereby the sum of the hydrophobicity
(clogP) and aromatic ring
count is proportional to caseum binding. These tools can be used to
ensure desirable lesion partitioning and guide the selection of optimal
regimens against tuberculosis