Respiratory ATP synthesis – the new generation of (myco-)bacterial drug targets

Tuberculosis causes approximately 2 million deaths per year and an estimated 1/3 of the world population harbors Mycobacterium tuberculosis in a dormant or latent form. To counteract development of drug-resistant mycobacterial strains the discovery of new drugs, validation of new target proteins, and understanding of drug/target interactions are essential. Energy metabolism has emerged as a new target-pathway for development of new anti-tubercular drugs. Previously, in collaboration with Tibotec/J&J we validated ATP synthase as target of the diarylquinolines, a new, promising class of anti-tuberculosis drugs. 

New developments concerning bacterial energy metabolism as drug target:

  • Strategies for new antibacterials against metabolically resting bacteria. In this paper we discuss the issue of bacterial metabolic resting states, observed for a variety of pathogenic bacteria, which display low susceptibility for most antibacterials. Based on our work we present examples of how bacterial metabolic states may be controlled, target pathways may be validated and screening on metabolically resting bacteria can be designed. A deeper understanding of bacterial metabolic states may provide valuable input for the design of efficient screening approaches in the discovery of new antibacterial agents.
  • Synergy of drugs acting on energy metabolism. Strong synergy has been found in mouse models for combinations of drugs either known or postulated to target energy metabolism, such as diarylquinolines, pyrazinamide and clofazimine. In this paper we investigate synergy between inhibitors of energy metabolism in in vitro settings.
  • Adaptations of ATP synthase in pathogenic bacteria? Several pathogenic bacteria have to deal with energetically unfavorable conditions such as low oxygen tensions in the human host. It is well conceivable that ATP synthases in these bacteria may carry idiosyncratic features that contribute to efficient ATP production. In this paper we discuss genetic and biochemical data on mycobacterial ATP synthase in M. tuberculosis that indicate an atypical subunit composition, and unusual regulatory features. A deeper understanding of the working of mycobacterial ATP synthase and its atypical features can provide insight in adaptations of bacterial energy metabolism. Moreover, pinpointing and understanding critical differences as compared with human ATP synthase may provide input for the design and development of selective ATP synthase inhibitors as antibacterials.