Helicobacter pylori is an important human pathogen with increasing antimicrobial resistance to standard-of-care antibiotics. Treatment generally includes a combination of classical broad-spectrum antibiotics and a proton-pump inhibitor, which often leads to perturbation of the gut microbiome and the potential for the development of antibiotic resistance. In this review, we examine reports, primarily from the past decade, on the discovery of new anti-H. pylori therapeutics, including approaches to develop narrow-spectrum and mechanistically unique antibiotics to treat these infections in their gastric niche. Compound series that target urease, respiratory complex I, and menaquinone biosynthesis are discussed in this context, along with bivalent antibiotic approaches that suppress resistance development. With increases in the understanding of the unique physiology of H. pylori and technological advances in the field of antibacterial drug discovery, there is a clear promise that novel therapeutics can be developed to effectively treat H. pylori infections.

© 2022 The Author(s). Published by Elsevier Ltd.