Oxysterols are oxidized derivatives of cholesterol with diverse biological properties that differ from those of parent cholesterol. Individual oxysterol characteristics vary significantly based on chemical composition, and small structural changes can have an outsized impact on properties in this chemical class. Among naturally occurring oxysterols, some are known only as passive and transient metabolites of cholesterol, while others have emerged as physiologically relevant signaling molecules, affecting diverse phenomena such as cholesterol homeostasis and immunological responses. MAX BioPharma, the inventors of the Oxysterol Therapeutics® platform, have engineered novel drug candidates in a wide range of therapeutic areas including metabolic and cardiovascular diseases, cancers, chronic inflammatory diseases, viral infections, and fibrotic disorders. Through a strategic collaboration with MAX BioPharma, Metaba has expanded its platform to pioneer Oxysterol-Based Antibiotics, unlocking new possibilities in combating drug-resistant infections. We have designed, tested, and identified novel oxysterol-based bactericidal compounds that kill drug-resistant Mtb. This innovative strategy was born from a hypothesis-driven approach to target cellular processes crucial to the survival and persistence of Mtb. Specifically, turning the ability of Mtb to utilize host cholesterol for energy and neutralize immunomodulatory oxysterols produced by host immune cells against itself. While these adaptations contribute to Mtb virulence, persistence, and treatment resistance, they have provided us with an opportunity to develop new bactericidal drugs because oxysterols and the parent cholesterol have structural and physicochemical similarities that likely facilitate their uptake. Oxysterols have the potential to establish a groundbreaking, new chemical class of Next-Generation Antibiotics, targeting not only Mtb but also other pathogenic bacteria.

The current standard of care (SOC) treatment for active, non-drug-resistant TB requires a combination of multiple antibiotics for a minimum of 4-9 months. This lengthy treatment period with significant side-effects increases the risk of non-adherence and contributes to the formation of drug-resistant strains. This highlights the urgent need for enhancing the effectiveness of current SOC antibiotics to reduce treatment duration, leading to increased adherence and improved patient outcomes. Using the power of metabolomics, Metaba’s scientists identified a previously untargeted, bacteria-specific enzyme, that is involved in the ability of Mtb to adapt and evade the full killing force of SOC antibiotics, allowing it to survive for longer periods of time. Inhibition of this enzyme was shown to enhance the therapeutic effect of current SOC antibiotics while reducing the rate of drug resistance mutations in Mtb. This strategy of employing adjuvant therapies together with current antibiotics holds significant promise for safer and more effective TB treatment.

Many infectious agents can persist in a dormant state within the human body, leading to chronic and recurrent infections, especially in immunocompromised individuals. The most susceptible population segment is the elderly whose innate immune system, the first line of defense against infections, has been weakened due to immunosenescence and inflammaging. Immunosenescence refers to age-related changes in the adaptive and innate immune systems that reduce efficacy over time, making it harder to mount responses against pathogens. Inflammaging is the chronic, low-grade inflammation that develops with age, contributing to immune dysfunction and increasing susceptibility to infections and diseases. Identification and development of immune enhancers that are safe and effective for use in elderly and immunocompromised individuals is of utmost importance for improved health outcomes in these populations. Metaba’s scientists have identified novel small molecule oxysterols that enhance immune cell function, for example, helping macrophages clear pathogens by producing antimicrobial factors, offering a safer and more effective approach to combating Mtb and other infectious agents.