A Comprehensive Overview of Antibacterial Agents for Combating Multidrug-Resistant Bacteria: The Current Landscape, Development, Future Opportunities, and Challenges.

Background/Objectives: Antimicrobial resistance poses a major public health challenge. The World Health Organization has identified 15 priority pathogens that require prompt development of new antibiotics. This review systematically evaluates the antibacterial resistance of the most significant bacterial pathogens, currently available treatment options, as well as complementary approaches for the management of infections caused by the most challenging multidrug-resistant (MDR) bacteria. For carbapenem-resistant Gram-negative bacteria, treatment options include combinations of beta-lactam antibiotics and beta-lactamase inhibitors, a novel siderophore cephalosporin, known as cefiderocol, as well as older antibiotics like polymixins and tigecycline. Treatment options for Gram-positive bacteria are vancomycin, daptomycin, linezolid, etc. Although the development of new antibiotics has stagnated, various agents with antibacterial properties are currently in clinical and preclinical trials. Non-antibiotic strategies encompass antibiotic potentiators, bacteriophage therapy, antivirulence therapeutics, antimicrobial peptides, antibacterial nanomaterials, host-directed therapy, vaccines, antibodies, plant-based products, repurposed drugs, as well as their combinations, including those used alongside antibiotics. Significant challenges exist in developing new antimicrobials, particularly related to scientific and technical issues, along with policy and economic factors. Currently, most of the alternative options are not part of routine treatment protocols. Conclusions and Future Directions: There is an urgent need to expedite the development of new strategies for treating infections caused by MDR bacteria. This requires a multidisciplinary approach that involves collaboration across research, healthcare, and regulatory bodies. Suggested approaches are crucial for addressing this challenge and should be backed by rational antibiotic use, enhanced infection control practices, and improved surveillance systems for emerging pathogens.