Biology subjects

Alivisatos, A.

Publications and source records attributed to Alivisatos, A..

3 recordsLinked to original sources

bioRxiv2025

Antibiotic dose-response curves can measure antibiotic activity against Mycobacterium abscessus and Mycobacterium peregrinum

Mycobacterium abscessus is a drug-resistant pathogen associated with poor clinical outcomes despite treatment with multidrug antibiotic regimens. Apart from clarithromycin, antimicrobial susceptibility testing (AST) results for Mycobacterium abscessus cannot guide antibiotic selection. AST involves measuring the minimum inhibitory concentration (MIC), which is allowed to span a four-fold range in concentration. This accepted variability of the MIC limits the clinical utility of AST. Antimicrobial dose-response curves, obtained by measuring the growth inhibition of a given organism to increasing concentrations of an antibiotic, can yield metrics of antibiotic activity that are less variable than the MIC. We used Clinical and Laboratory Standards Institute growth conditions for rapid-grower nontuberculous mycobacteria to generate 990 dose-response curves across three time points (72 hours, 96 hours, and 120 hours) for six guideline-recommended (clarithromycin, amikacin, cefoxitin, linezolid, tigecycline, and clofazimine) and five new (omadacycline, tedizolid, SPR719, SQ109, and bedaquiline) antibiotics against Mycobacterium abscessus subspecies abscessus ATCC 19977 and Mycobacterium peregrinum ATCC 700686. We established the fit of the dose-response curve (R2) as a quality control metric. Using the geometric standard deviation and median coefficient of variation, we demonstrated that the IC50 and IC75 (antibiotic concentrations corresponding to 50% and 75% growth inhibition, respectively) are less variable than the MIC. We identified time-dependent changes in dose-response curve metrics that allow the detection of inducible clarithromycin resistance with only five days of incubation. This study demonstrates the potential of dose-response curves in measuring antibiotic activity against Mycobacterium abscessus.

microbiology↗

bioRxiv2024

Integration of multi-modal measurements identifies critical mechanisms of tuberculosis drug action

Treatments for tuberculosis remain lengthy, motivating a search for new drugs with novel mechanisms of action. However, it remains challenging to elucidate the direct targets of a drug, and even more so, to determine which disrupted cellular processes lead to bacterial killing. We developed a computational tool, DECIPHAER (DEcoding Cross-modal Information of PHarmacologies via AutoEncodeRs), to select the important correlated transcriptional and morphological responses of Mycobacterium tuberculosis to drug treatments. By finding a reduced feature space from these measurements, DECIPHAER highlighted essential features of Mtb cellular damage such as phosphosugar stress and inhibition of translation and DNA replication. After training, DECIPHAER provides cell-death-relevant insight into single-modal datasets, enabling interrogation of drug treatment responses for which transcriptional data are unavailable. Using morphological data alone with DECIPHAER, we discovered that respiration inhibition by the poly-pharmacological drugs, SQ109 and BM212, can influence cell death more than their effects on the cell wall. This study demonstrates that DECIPHAER can extract the critical shared information from multi-modal measurements to identify cell death-relevant mechanisms of TB drugs.

microbiology↗

bioRxiv2022

Convergent deployment of ancestral programs during the evolution of mammalian flight membranes

Lateral flight membranes, or patagia, have evolved repeatedly in diverse mammalian lineages. While little is known about patagium development, its recurrent evolution may suggest a shared molecular basis. By combining transcriptomics, developmental experiments, and mouse transgenics, we demonstrate that lateral WNT5A expression in the marsupial sugar glider (Petaurus breviceps) promotes the differentiation of its patagium primordium. We further show that this function of WNT5A reprises ancestral roles in skin morphogenesis predating mammalian flight and has been convergently employed during patagium evolution in eutherian bats. Moreover, we find that many genes involved in limb development have been re-deployed during patagium outgrowth in both the sugar glider and bat. Taken together, our findings reveal that deeply conserved molecular toolkits underpin the evolutionary transition to flight in mammals.

developmental biology↗