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 multidrug-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 "nontraditional" 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 nontraditional), with 28 in phase 1, 32 in phase 2, 12 in phase 3, and 4 under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) were against mycobacteria, 15 (20%) were against C. difficile, and 4 (5%) were nontraditional agents with broad-spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores, and 4 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 research and development (R&D) should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.

Keywords: Clostridioides difficile; WHO priority pathogens; antibacterial pipeline; antibiotic; clinical trials; mycobacteria; nontraditional; traditional; tuberculosis.

FIG 1

List of the WHO’s critical-, high-, and medium-priority pathogens (3, 4) and mycobacteria. *, Enterobacteriaceae (Escherichia coli, Enterobacter spp., and Klebsiella pneumoniae) and Enterobacterales (Morganella spp., Proteus spp., Providencia spp., and Serratia spp.).

FIG 2

Structures of antibacterial drugs approved worldwide since 2017 and their approved indications and targeted priority pathogens with country and year of first approval.

FIG 3

Number of traditional and nontraditional antibacterials by (A) development phase and (B) development against WHO priority pathogens, TB and NTM, C. difficile, and G+ve/G−ve.

FIG 4

Traditional and nontraditional antibacterials categorized by development phase and activity against WHO critical pathogens, WHO high- and medium-priority pathogens TB and NTM, C. difficile, and nontraditional nonspecific G+ve/G−ve activity.

FIG 5

Antibacterials with new pharmacophores not previously found in human antibacterial drugs by target class, target, antibacterial name (current development phase), and antibacterial class. Abbreviations: TB, tuberculosis; Sa, S. aureus; Cd, C. difficile, Ec, E. coli; Ng, N. gonorrhoeae; NTM, nontuberculosis mycobacteria; G−, Gram-negative bacteria.