Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020

Abstract

The World Health Organization (WHO) has warned that our current arsenal of antibiotics is not innovative enough to face impending infectious diseases, especially those caused by multidrug-resistant Gram-negative pathogens. Although the current preclinical pipeline is well stocked with novel candidates, the last U.S.

Essential Gene Phenotypes Reveal Antibiotic Mechanisms and Synergies inAcinetobacter baumannii

“…Gram-negative pathogens, including Acinetobacter baumannii, have become increasingly recalcitrant to antibiotic treatment. The emergence of antibiotic resistance alongside a stalled pipeline for additional classes of Gram-negative targeting drugs threaten to precipitate a global health crisis in which many infections become untreatable (1). A. baumannii causes serious infections in hospitalized patients and is considered an urgent threat for its ability to evade targeting by antibiotics of last resort (2).…”

Essential Paralogous Proteins as Potential Antibiotic Multitargets in Escherichia coli

“…Despite increasing resistance to existing antibiotics ( 79 ), novel targets have been underrepresented in recently approved antibiotics, with no novel-mechanism classes launched for Gram-negative pathogens in nearly 60 years ( 80 ). The goal of this study was to identify potential novel multitargets for antibiotic development by identifying all essential gene products having at least one additional essential paralog in the model Gram-negative pathogen Escherichia coli .…”

Emerging Target-Directed Approaches for the Treatment and Diagnosis of Microbial Infections

“…The presence of more effective and less structurally complex broad-spectrum β-lactams on the market and the lack of Gram-positive activity, along with the insufficient market potential and high production costs, were announced as the main reasons . But due to the changing landscape of the Gram-negative arena, driven largely by antibiotic resistance, this siderophore conjugate approach received renewed attention in 2010 by Basilea Pharmaceutica International, which reported the first iron-carrier antibiotic, BAL30072 (Figure ), that evolved to clinical studies. , This monobactam conjugate, with an appended dihydroxypyridinone moiety for iron chelation, exhibited in vitro bactericidal activity against P. aeruginosa , Acinetobacter species, and Enterobacteriaceae , similar to that of other monocyclic β-lactams, including against strains that produce metallo-β-lactamases. , Positive toxicity studies in rats and marmosets, along with a lack of confidence in the candidate’s success, led to the discontinuation of this candidate . Later, in 2011, a monobactam with a hydroxypyridone iron chelating group, MC-1 (Figure ), was reported by Pfizer. , This U-78608 analogue exhibited remarkable antipseudomonal activity both in vitro and in vivo . , However, MC-1 was revealed to be chemically unstable and susceptible to hydrolysis, which limited further research …”