The prevalence of resistant bacteria is increasing rapidly and in contrast, antibiotic research and development (R & D) in big Pharma has become mostly abandoned. If the resistance problem is not addressed, it is estimated that as many as 10 million people will die each year due to infections caused by resistant bacteria in 2050 (the so called, silent Tsunami). The 2022 Global Antimicrobial Resistance report by the World Health Organization (WHO) underlines the worldwide alarming rise of drug-resistant bacteria, for which new antibiotics are urgently needed.
For instances, patients with infections due to the vancomycin-resistant Enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) were found to be at high risk of mortality and prolonged hospitalization, burdening the healthcare systems and economy. Moreover, infections with the Gram-negative bacteria Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii are classified among the most serious and the pathogens are becoming increasingly multidrug-resistant (MDR). Furthermore, Escherichia coli causing urinary tract infections has become less susceptible to standard antibiotic treatment including ampicillin, co-trimoxazole, and fluoroquinolones in 20% of the patients in 2020.
Alarmingly, the antibiotic development pipeline only contains 32 antibacterials against the WHO priority pathogens and only two of these are active against MDR Gram-negative bacteria. Addressing Gram-negative bacteria is particularly difficult as they have an additional outer cell membrane that prevents the penetration of large, hydrophobic compounds while hydrophilic compounds are hindered by the inner membrane. In addition, bacteria have efflux pumps to rapidly remove toxic compounds that have found their way inside the cell. This makes antibiotic development extremely challenging. Additionally, most compounds in the pipeline are derivatives of antibiotics with a known mode-of-action (MoA), to which resistance mechanisms already exist. Thus, the development on innovative compound classes acting through an unprecedented MoA is urgently required to tackle the rising antibiotic resistance crisis.
In order to tackle this problem of antibiotic-innovation gap, we are concerned with developing novel small molecule antibiotics inhibiting new essential targets in bacteria. Our strategy can be beneficial for the treatment of bacterial infections in general and those caused by MDR pathogens in particular. In this context, we are interested in targeting the bacterial sliding clamp (DnaN), a replisome component pivotal for DNA synthesis and repair. DnaN is an emerging and very promising target in terms of efficacy, broad-spectrum activity, selectivity, and low frequency of resistance development. In this Proof-of-Concept project, we pursued to build on our promising findings from the ERC start grant (NovAnI) in order to advance our discovered novel class of DnaN inhibitors towards a lead candidate suitable for the preclinical development, under mentorship of a pharmaceutical industry partner.
