Molecular resistance mechanisms to newly approved antibiotics (2017–2025) in WHO priority pathogens

TL;DR

This paper reviews how dangerous bacteria are quickly developing resistance to new antibiotics approved since 2017, highlighting the urgent need for global strategies to combat antimicrobial resistance.

Contribution

The paper systematically compiles molecular resistance mechanisms against 15 new antibiotics in WHO priority pathogens from 2017–2025.

Findings

Resistance mechanisms include enzymatic inactivation, efflux pumps, target site modifications, and reduced membrane permeability.

New antibiotics often face resistance via pre-existing genetic pathways adapted to novel drug structures.

Emerging resistance highlights the need for advanced diagnostics, bioinformatics, and global 'One Health' strategies.

Abstract

The relentless rise of antimicrobial resistance (AMR) poses a critical threat to global public health, rendering once-effective therapies obsolete. In response, several novel antibiotics have been developed in recent years. This review systematically summarizes the molecular resistance mechanisms that World Health Organization (WHO) priority bacterial pathogens have already deployed against the 15 new antibiotics approved between 2017 and 2025, including β-lactam/β-lactamase inhibitors (cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam), tetracycline derivatives (eravacycline, omadacycline), a pleuromutilin (lefamulin), an aminoglycoside (plazomicin), and a fluoroquinolone (delafloxacin). We detail how pathogens utilize four primary strategies to overcome these last-line agents: enzymatic inactivation (e.g., by KPC, NDM, OXA-48, and Tet(X) variants), efflux pump overexpression (e.g., AdeABC, AcrAB-TolC, MexAB-OprM), modifications of target sites (e.g., PBP3, RpoB, ribosomal proteins/L3, and QRDR mutations), and reduced membrane permeability. Evidence consistently demonstrates that resistance emerges rapidly, often through pre-existing genetic pathways repurposed against the new chemical structures. This analysis underscores the paradoxical reality of antimicrobial development: the introduction of new therapies simultaneously selects for and elucidates new resistance mechanisms. Preserving the efficacy of these essential drugs thus necessitates a multifaceted, globally coordinated “One Health” strategy. Finally, we discuss how the growing complexity of AMR mechanisms is driving the need for advanced diagnostic tools, exploring the pivotal role of bioinformatics and artificial intelligence in predicting resistance and closing knowledge gaps.