The global preclinical antibacterial pipeline

Abstract

| Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of nontraditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work , focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

“…Taken together, the activity spectrum of ZN148 in combination with carbapenems, in vivo efficacy and limited in vivo toxicity demonstrate that ZN148 has the potential to enter pre-clinical studies for further development. Furthermore, as a modular and easy-to-synthesize MBL inhibitor that restores the activity of carbapenems towards a range of clinically important Gram-negative MDR pathogens, ZN148 is well placed to enter the clinical development pipeline along with other promising recently approved molecules (47) in meeting the urgent, therapeutic challenge of global importance.…”

Strategies to Combat Persistent Infectious Diseases

“…Giving them a closer look would be necessary in order to combat persistent and re-incident bacterial infections caused by resistant pathogens. Theuretzbacher et al [88] wrote a interesting review where they analyzed some of the new treatments that have been summarized all along the present review, together with vaccines and immune-modulators-based therapies.…”

Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

“…A closer look at such strategies is necessary in order to combat persistent and re-incident bacterial infections caused by resistant pathogens. In an interesting recent review, Theuretzbacher and colleagues examined some of the new treatments summarized in the present review, together with vaccines and immune-modulator-based therapies [87].…”