Interrogation of sidb-dependent septation for echinocandin potentiation in invasive aspergillosis treatment - invasive pulmonary aspergillosis (IPA), caused mainly by aspergillus fumigatus, is a…

The National Institute of Allergy and Infectious Diseases awarded the University of Tennessee Health Science Center $163,852 on November 1, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct research on the septation initiation network (SIN) kinase cascade in Aspergillus fumigatus, with the goal of enhancing echinocandin antifungal efficacy against invasive pulmonary aspergillosis.

The research interrogates SIDB-dependent septation mechanisms that confer echinocandin resistance in A. fumigatus, a pathogen causing invasive pulmonary aspergillosis with mortality rates up to 90 percent. The investigator identified that septation-deficient Aspergillus mutants are highly susceptible to echinocandins in vitro and struggle to invade mouse lung tissue during infection. The study focuses on the terminal SIN kinase SIDB, a putative nuclear DBF2-related kinase, and its putative binding partner MOBA, to understand how loss of MOBA phenocopies pathway inactivation and could inform strategies to potentiate echinocandin efficacy against this difficult-to-treat infection.

Performance of the work occurs at the University of Tennessee Health Science Center in Memphis, Tennessee, with an ultimate completion date of April 14, 2027. The assistance type is a Project Grant. This is an investigator-initiated award within NIAID's broader portfolio supporting basic and applied research in infectious disease mechanisms at academic medical centers and research institutions.

Interrogation of sidb-dependent septation for echinocandin potentiation in invasive aspergillosis treatment - invasive pulmonary aspergillosis (IPA), caused mainly by aspergillus fumigatus, is a severe infection with mortality rates up to 90%. These infections are characterized by invasive penetration of septate hyphae into host tissues. As resistance to antifungal drugs becomes more common, these difficult-to-treat infections are at risk of becoming more so. The echinocandin antifungal class are well-tolerated cell wall biosynthesis inhibitors yet are limited in use against IPA. This is mostly due to their fungistatic anti-aspergillus activity and association with a paradoxical induction of growth at high concentrations leading to frequent treatment failure. Enhancing echinocandin efficacy carries the promise of significantly improving patient outcomes for IPA. In a screen for protein kinases that are required for survival in the face of echinocandin stress, our laboratory identified that septation-deficient aspergillus mutants are highly susceptible to echinocandins in vitro and, excitingly, struggle to invade mouse lung tissue during infection. We found each member of the septation initiation network (SIN) kinase cascade to be required for septation, intrinsic echinocandin resistance, and virulence of a. Fumigatus. My preliminary data have uncovered the terminal SIN kinase, sidb, as critically important for further study. Sidb is a putative nuclear DBF2-related (NDR) kinase that is predicted to require multiple steps for full activation. The first of these steps typically includes the N-terminal binding of a conserved MOB-family protein to stabilize protein conformation and enable downstream phosphorylation events. From a genetic study of five candidate SIN regulatory proteins, I have found that loss of only the putative sidb binding partner, moba, results in a mutant that completely phenocopies pathway inactivation via loss of a SIN kinase. A moba deletion mutant displayed aseptate hyphae and was avirulent in a mouse model of IPA. Importantly, loss of moba resulted in fungicidal echinocandin activity. Therefore, either loss of the sidb kinase or of its major activating partner, moba, results in echinocandin hypersensitivity and impaired virulence. Taken together, our findings support the idea that inhibition of (I) sidb kinase activity, (II) sidb/moba binding, or (III) downstream effectors of sidb/moba could each prove to be successful avenues for improving anti-aspergillus echinocandin activity as well as blocking deadly tissue- invasive growth. My objective in this proposal is to define the roles of sidb in pathogenic growth by methodically delineating its activation and important effectors during septation and echinocandin treatment. We will achieve this objective by identifying phosphorylation events that are necessary for sidb-dependent septation (aim 1) and uncovering novel SIN effectors regulating septation and echinocandin resistance (aim 2). This work will provide critical understanding of how sidb contributes to septum formation towards aspergillus pathogenesis. Septation blockage via sidb inhibition could be a promising way to increase echinocandin activity for IPA patients. This knowledge can provide key context for developing novel antifungal drugs targeting septation machinery.