The CARB-X Portfolio of Nontraditional Antibacterial Products

Duffy, Erin M; Buurman, Ed T.; Chiang, Su L.; Cohen, Nadia; Uria-Nickelsen, Maria; Alm, Richard A.

doi:10.1021/acsinfecdis.1c00331

Cited by 13 publications

(12 citation statements)

References 30 publications

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“…These cationic peptides selectively target and attack the anionic membranes of bacterial pathogens 13 , 14 . Encouragingly, a recent update from the CARB-X antibiotic accelerator reports that direct-acting peptides account for approximately 11% of their portfolio, showing renewed industry interest in these compounds to overcome multidrug resistant bacterial strains 15 .…”

Section: Introductionmentioning

confidence: 99%

An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics

Cama

Nahas

Fletcher

et al. 2022

Sci Rep

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Antimicrobial resistance challenges the ability of modern medicine to contain infections. Given the dire need for new antimicrobials, polypeptide antibiotics hold particular promise. These agents hit multiple targets in bacteria starting with their most exposed regions—their membranes. However, suitable approaches to quantify the efficacy of polypeptide antibiotics at the membrane and cellular level have been lacking. Here, we employ two complementary microfluidic platforms to probe the structure–activity relationships of two experimental series of polypeptide antibiotics. We reveal strong correlations between each peptide’s physicochemical activity at the membrane level and biological activity at the cellular level. We achieve this knowledge by assaying the membranolytic activities of the compounds on hundreds of individual giant lipid vesicles, and by quantifying phenotypic responses within clonal bacterial populations with single-cell resolution. Our strategy proved capable of detecting differential responses for peptides with single amino acid substitutions between them, and can accelerate the rational design and development of peptide antimicrobials.

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Section: Introductionmentioning

confidence: 99%

An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics

Cama

Nahas

Fletcher

et al. 2022

Sci Rep

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“…Renewed focus to identify new antibacterial drugs against MDR bacteria, combined with several recent financing mechanisms, has helped to increase the number of traditional and nontraditional antibacterial agents moving through the preclinical ( 94 ) and clinical development pipelines ( 41 , 90 , 95 , 96 ). Despite a total of 76 antibacterial candidates (45 traditional and 31 nontraditional) being evaluated in clinical trials on 30 June 2021, our analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical-priority pathogens.…”

Section: Discussionmentioning

confidence: 99%

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

Butler

Gigante²,

Sati³

et al. 2022

Antimicrob Agents Chemother

Self Cite

172

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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.

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“…This implies that SMEs are facing, with limited capacity, the risks and down-turns of product failure in the early stages, despite the fact that this research stage is the mainstay in R&D, to ensure the sustainability of new antibacterial drug candidates in the development pipeline. The main funding programs are focusing on the pre-clinical stages as a result of private–public partnerships, such as the Global Antibiotic Research and Development Partnership (GARDP), Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) [ 160 , 237 , 238 ], Innovative Medicines Initiative (IMI), and Drugs for Neglected Diseases Initiative (DNDi), in addition to international as well as national non-profit organizations and government programs [ 12 ]. Multiple incentives are available to boost R&D initiatives, which may or may not be efficient, depending on the context and framework.…”

Section: Antibiotics Research and Development: Incentives And Barriersmentioning

confidence: 99%

Antibiotic Discovery and Resistance: The Chase and the Race

et al. 2022

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The history of antimicrobial resistance (AMR) evolution and the diversity of the environmental resistome indicate that AMR is an ancient natural phenomenon. Acquired resistance is a public health concern influenced by the anthropogenic use of antibiotics, leading to the selection of resistant genes. Data show that AMR is spreading globally at different rates, outpacing all efforts to mitigate this crisis. The search for new antibiotic classes is one of the key strategies in the fight against AMR. Since the 1980s, newly marketed antibiotics were either modifications or improvements of known molecules. The World Health Organization (WHO) describes the current pipeline as bleak, and warns about the scarcity of new leads. A quantitative and qualitative analysis of the pre-clinical and clinical pipeline indicates that few antibiotics may reach the market in a few years, predominantly not those that fit the innovative requirements to tackle the challenging spread of AMR. Diversity and innovation are the mainstays to cope with the rapid evolution of AMR. The discovery and development of antibiotics must address resistance to old and novel antibiotics. Here, we review the history and challenges of antibiotics discovery and describe different innovative new leads mechanisms expected to replenish the pipeline, while maintaining a promising possibility to shift the chase and the race between the spread of AMR, preserving antibiotic effectiveness, and meeting innovative leads requirements.

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The CARB-X Portfolio of Nontraditional Antibacterial Products

Cited by 13 publications

References 30 publications

An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics

An ultrasensitive microfluidic approach reveals correlations between the physico-chemical and biological activity of experimental peptide antibiotics

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

Antibiotic Discovery and Resistance: The Chase and the Race

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