Antibiotics in the clinical pipeline as of December 2022

Abstract

The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed.

Using Machine Learning to Predict the Antibacterial Activity of Ruthenium Complexes**

“…Notably, there has been a small but encouraging increase in recent years. [5] As the conventional sources for antibiotics, i.e. natural products and small organic molecules are not enough to contain the worsening antimicrobial resistance (AMR) problem, novel approaches are urgently needed.…”

Identification and targeting of microbial putrescine acetylation in bloodstream infections

“…Treatment options for BSI and AMR-infections more broadly remain limited both by a narrow repertoire of targets and challenges in drug development that have slowed the pipeline of new antimicrobial agents [14][15][16] .…”

“…These microbes are members of the World Health Organization Priority 1 group of pathogens, recognized as primary drivers of AMR-associated mortality 1 and priority targets for antibiotic development. Treatment options for BSI and AMR-infections more broadly remain limited both by a narrow repertoire of targets and challenges in drug development that have slowed the pipeline of new antimicrobial agents 14-16 .…”

Development of Novel Membrane Disrupting Lipoguanidine Compounds Sensitizing Gram-Negative Bacteria to Antibiotics

“…The scarcity of new antibiotic development is a significant contributing factor to the rise of antibiotic resistance, , and thus, the development of new treatments for bacterial infections is considered critical by the World Health Organization (WHO). While some new antibiotic classes targeting Gram-positive bacteria have been introduced to the market within the last 20 years, − only a few antibiotics that target Gram-negative bacteria are currently in the clinical pipeline. − Such failure is largely attributed to the inability of many drugs to cross both the Gram-negative outer membrane (OM) and the inner membrane (IM) and to accumulate within these bacteria. Indeed, even though the molecular targets of many Gram-positive active antibiotics are also present in Gram-negative bacteria, the Gram-negative OM acts as a further barrier preventing the entry of such drugs to the cell. , OM disrupting or perturbing agents, such as peptides, the chelating agent ethylenediaminetetraacetic acid (EDTA), the antiprotozoal drug pentamidine, the antifungal agent amphotericin B, or the cationic antibiotics, − have shown their potential in sensitizing Gram-negative bacteria to the action of Gram-positive active antibiotics.…”