Fighting antibiotic-resistant superbugs with anti-persister compounds targeting the stringent response
Pathogenic antibiotic-resistant “superbugs” are increasing at an alarming pace. Persistence to antibiotics favours the emergence of resistance as mutations increasing antibiotic tolerance favour selection of resistance mutations. Persisters constitute subpopulations of cells that can withstand bactericidal antibiotics and are considered as a primary source of infections since they are difficult or impossible to eradicate with conventional antibiotics. Persister bacteria are encountered in a variety of chronic pathologies, including cystic fibrosis, pneumonia and tuberculosis. Thus the impact of persistence on public health is enormous and there is a pressing need to develop treatments to kill persisters. The existence of a causal link between persisters and persistent infections was demonstrated for S. typhimurium, whose survival inside the host relies on ppGpp. Compounds capable of killing persisters could sterilise S. aureus cultures and cured methicillin-resistant S. aureus (MRSA)infected mice. Thus targeting the enzymes that regulate ppGpp is an interesting and unexplored route to develop new antibiotics active against persisters. This project aims to target key steps in the mechanism of ppGpp synthesis and hydrolysis in a variety of pathogenic bacteria. In an integrative biochemistry, structural and cellular biology based approach we will uncover novel mechanistic aspects of persistence, deliver novel metabolic biosensors for single-cell analysis and methodologies to study persisters in human pathogens, and discover and validate novel compounds with antipersister action.
- Abel Garcia-Pino, Université Libre de Bruxelles, Belgium (Coordinator)
- Leonardo Pardo, Universitat Autònoma de Barcelona, Spain (Partner)
- Ewa Laskowska, University of Gdansk, Poland (Partner)
- Olivier Neyrolles, Université de Toulouse, France (Partner)
Since the discovery of penicillin by Fleming in the late 1920s, antibiotics have revolutionized the field of medicine and human society in general. However, the antibiotic development pipeline dried out in the late 1980s and we have now reached a critical point where many antibiotics are no longer effective against even the simplest infections. In this context, infectious diseases are now the second leading cause of death in the world with 17 million people dying each year from bacterial infections worldwide. Pathogenic antibiotic-resistant “superbugs” are a particularly problematic emergent global health threat growing at an alarming pace. These superbugs are typically highly antibiotic tolerant and multi-drug resistant. One of the survival strategies of these pathogens is to enter in a seemingly “dormant” state that suspends cell division known as persister state. Disguised as persisters, bacteria become highly tolerant to antibiotics and stress in general, therefore targeting persisters has become one of the modern challenges of microbiology. These non-growing bacteria are encountered in a variety of chronic pathologies, including cystic fibrosis, pneumonia and tuberculosis (TB). Thus the impact of persistence on public health is thus enormous and there is a pressing need to develop treatments to kill persisters. It has been previously shown that a strategy that addresses the persistence problem is a promising approach in the fight against multi-drug resistant superbugs. Therefore this project aims to target key steps in the mechanisms of pathogenic bacteria to regulate stress that are involved in persistence from integrative biochemistry-, structural and cellular biology-based perspective to discover novel compounds that could lead to the development of new types of antibiotics.
- Nature Chemical Biology, 2020. A nucleotide-switch mechanism mediates opposing catalytic activities of Rel enzymes
- Front Microbiol, 2020. The C-Terminal RRM/ACT Domain Is Crucial for Fine-Tuning the Activation of ‘Long’ RelA-SpoT Homolog Enzymes by Ribosomal Complexes
- Acta Crystallogr F Struct Biol Commun, 2019. The Rel stringent factor from Thermus thermophilus: crystallization and X-ray analysis
- Research Square, 2022. The structure of SpoT reveals evolutionary tuning of enzymatic output through constraint of the conformational landscape
- Nature Chemical Biology, 2022. Structure of SpoT reveals evolutionary tuning of catalysis via conformational constraint