Analysis of the Clinical Pipeline of Treatments for Drug-Resistant Bacterial Infections: Despite Progress, More Action Is Needed

Abstract

There is an urgent global need for new strategies and drugs to control and treat multi-drug resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes ‘traditional’ and ‘non-traditional’ antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens, mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 non-traditional) with 28 in Phase 1, 32 in Phase 2, 12 in Phase 3 and four under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) against mycobacteria, 15 (20%) against C. difficile and 4 (5%) are non-traditional agents with broad spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores and four of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical Priority Pathogens. We believe that future antibacterial R&D should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

“…Woodward ( Ernest et al, 1978 ). The penem class is one of a few β-lactam antibiotics still being researched, and includes faropenem, ritipenem, and sulopenem ( Batchelder et al, 2020 ; Butler et al, 2022 ; Sato et al, 2022 ). While no members of the thiapenem class are currently used in United States clinical settings, safety and efficacy data required for FDA approval are forthcoming.…”

Molecular mechanism of plasmid-borne resistance to sulfonamides

“…The copyright holder for this preprint this version posted June 30, 2022. ; https://doi.org/10. 1101/2022 To gain an understanding of the sul incurred resistance mechanism we first characterize the catalytic properties of the Sul enzymes in comparison to DHPS. We purified the Sul1, Sul2 and Sul3 enzymes recombinantly expressed in E. coli along with DHPS from the same species (EcDHPS) as an archetype for folP encoded enzymes.…”

Bactericidal Activity of Sodium Bituminosulfonate against Staphylococcus aureus

“…In 2019, MRSA caused more than 100,000 deaths and 3.5 million disability-adjusted life-years attributable to AMR [ 5 ]. Despite some progress achieved in the antibacterial pipeline in recent years, the pipeline outlook remains unfavorable [ 6 , 7 ]. In the context of a scarcity of new antimicrobial treatments, the re-examination of old substances with antimicrobial activity has potential value [ 8 ].…”