An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

Triplex-forming oligonucleotides constitute an interesting DNA sequence-specific tool that can be used to target cleaving or cross-linking agents, transcription factors or nucleases to a chosen site on the DNA. They are not only used as biotechnological tools but also to induce modifications on DNA with the aim to control gene expression, such as by site-directed mutagenesis or DNA recombination. Here, we report the state of art of the triplex-based anti-gene strategy 50 years after the discovery of such a structure, and we show the importance of the actual applications and the main challenges that we still have ahead of us.

The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins—readers, writers, and erasers—are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.