Davies, J. J. | bioRxiv Science

bioRxiv2026

BacPROTACs outperform inhibitors in Mycobacterium tuberculosis

Antibiotic discovery has long relied on occupancy-driven inhibition, leaving a vast number of potential bacterial targets undrugged.1 Targeted protein degradation offers a mechanistically distinct alternative to inhibition, yet its application to antibacterial drug discovery remains largely unexplored.2-4 Here we describe the development of first-in-class heterobifunctional bacterial proteolysis targeting chimeras (BacPROTACs) directed against an essential Mycobacterium tuberculosis protein, 4-phosphopantetheinyl transferase (PptT).5 Leveraging the modular architecture of BacPROTACs, we repurposed PptT inhibitors by incorporating them into degraders, yielding compounds with markedly improved antimycobacterial activity. Integrating in vitro and cellular approaches, we developed a characterisation pipeline to assess protein degradation in bacteria, applicable to future BacPROTAC programmes. Our study establishes targeted protein degradation as a strategy for antibacterial drug discovery.

microbiology↗

bioRxiv2023

Balance of Activity during a Critical Period Tunes a Developing Network

Developing neural circuits are influenced by activity and are especially sensitive to changes in activity during critical periods (CPs) of development. Changes occurring during a CP often become locked-in so that they affect the mature network. Indeed, several neurodevelopmental disorders have been linked to excessive activity during such periods. It is, therefore, important to identify those aspects of neural circuit development that are influenced by neural activity during a CP. In this study, we take advantage of the genetic tractability of Drosophila to show that activity perturbation during an embryonic CP permanently alters properties of the locomotor circuit. Specific changes we identify include increased synchronicity of motoneuron activity, and greater strengthening of excitatory over inhibitory synaptic drive to motoneurons. These changes are sufficient to reduce network robustness, evidenced by increased sensitivity to induced seizure. We also show that we can rescue these changes when increased activity is mitigated by inhibition provided by mechanosensory neurons. Similarly, we demonstrate a dose-dependent relationship between inhibition experienced during the CP, and the extent to which it is possible to rescue the hyperexcitable phenotype characteristic of the parabss mutation. This suggests that developing circuits must be exposed to a properly balanced sum of excitation and inhibition during the CP to achieve normal mature network function. Our results, therefore, provide novel insight into how activity during a CP shapes specific elements of a circuit, and how activity during this period is integrated to tune neural circuits to the environment in which they will likely function.

neuroscience↗