Designing effective adjunctive chemotherapy against drug-resistant tuberculosis (TB) and TB-like respiratory diseases

Overview and rationale: Antimicrobial resistance (AMR) threatens the control of an ever-increasing range of infectious diseases. We risk impeding drug research and offering therapy for drug-resistant tuberculosis (TB) caused primarily by Mycobacterium tuberculosis and TB-like respiratory diseases (such as asthma, chronic obstructive pulmonary disease/COPD, and cystic fibrosis) caused by opportunistic non-tuberculous mycobacteria (NTM) unless we refocus immediately. Mycobacteria are unique in their physiology, endogenous metabolism, immune evasion, dormancy and resuscitation, and they have proven to cause extreme drug resistance. HIV-TB co-infections further aggravate the TB pandemic amongst HIV-positive patients. Therefore, it is critical to accelerate the development of more effective combination therapy regimes. Context of the research: AMR in tuberculosis (TB) and TB-like respiratory diseases pose challenges in combating lung infections through existing treatment. Failure to treat a patient effectively with first-line anti-tubercular drugs mandates the use of a gruelling regimen with second-line drugs, with drawbacks including inflammation and tissue damage at the site of infection. Repurposing drugs presents an effective alternative to the time-consuming and expensive task of discovering new compounds. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) generally used as anti-inflammatory agents, have been reported to show anti-tubercular activity. Carprofen demonstrated good chemotherapeutic potential in shortening TB chemotherapy due to its additional bactericidal mechanisms of antibiotic action. Furthermore, our recent research has identified several prospective targets of carprofen on mycobacteria including efflux pump inhibition and biofilm disruption, key intrinsic mechanisms of antimicrobial resistance in mycobacterial infections. The promise of effective, shorter treatment regimens using first-line drugs in conjunction with carprofen is thus enticing. The primary aim of this proposal is to integrate multidisciplinary research expertise to accelerate the development of new antibiotic treatments to tackle drug-resistant infections. This will be achieved through defined tasks assigned under interconnected work packages to (a) investigate carprofen's anti-tuberculosis mechanisms of bactericidal action to validate its therapeutic potential as an adjunctive to first-line anti-TB drugs and its ability to reverse AMR; (b) design, synthesise and optimise lead carbazole-carboline scaffolds with improved bactericidal efficacy; (c) develop carprofen into nanosized formulation lung-delivery systems for enhanced targeted distribution and therapeutic efficacy with minimum metabolism and dose requirement; (c) conduct pharmacokinetics, pharmacodynamics and toxicity studies on infected mice model to advance the selected lead for further drug development. Potential applications and immediate benefits: The outcomes will be applied to disseminate and manage the multidisciplinary project with outreach, and impact activities on a global scale. Identification of new chemical leads with potent anti-tuberculosis activity and/or the ability to reverse AMR will accelerate further research into lead optimisation and provide a pipeline for clinical trials. Formulation of these molecules to a lung-targeted delivery system will provide direct reach; and will serve as an adjunctive chemotherapy for TB and related infections. This approach is consistent with the WHO's "End TB Strategy", which seeks to reduce TB incidence by 90% by 2035 and with the UKRI's mission to combat infectious diseases worldwide.