The antibiotic resistance crisis and the development of new antibiotics, by Harald Brüssow, highlight the urgent need for novel antibiotics due to the global burden of disease, which estimates 14 million infection-related deaths annually, with 1.3 million attributed to antibiotic resistance. The antibiotic development era peaked in the 1930s–1960s, but recent failures in screening chemical libraries and high development costs have led to a decline in pharmaceutical interest. Despite scientific advancements in defining chemical properties to overcome Gram-negative pathogen permeation barriers, limited financial resources hinder progress. The Global Burden of Disease (GBD) reports emphasize the significance of antibiotic resistance, with 1.3 million deaths attributed to it in 2019. The GBD 2019 report identified the top diseases by age-standardized disability-adjusted life years (DALYs), showing that infectious diseases remain a major cause of death, particularly in children. The report also highlights the disparity in research funding for infectious diseases compared to HIV. The antibiotic resistance crisis is further exacerbated by geographical variations in mortality rates and the emergence of drug-resistant pathogens. The European and US perspectives reveal significant numbers of antibiotic-resistant infections and deaths, with the US reporting 2.9 million infections annually. The GBD 2019 report projects 10 million antibiotic-resistant deaths by 2050, underscoring the need for new antibiotics. The development of new antibiotics has faced challenges, including the limitations of the Waksman platform and synthetic chemistry approaches. Recent research has focused on exploring 'unculturable' bacteria, leading to the discovery of teixobactin and clovibactin, which show promise against Gram-positive pathogens. Physicochemical approaches to antibiotic permeation have been explored, with studies on E. coli and P. aeruginosa revealing key criteria for membrane permeability. Efflux pump inhibitors and synthetic antibiotics based on target structure data have also been developed, with compounds like arylomycin and cresomycin showing efficacy against resistant pathogens. The development of new antibiotics remains challenging due to scientific and economic barriers, but recent advances in modular synthesis and targeting bacterial outer membrane components offer promising avenues for future research.The antibiotic resistance crisis and the development of new antibiotics, by Harald Brüssow, highlight the urgent need for novel antibiotics due to the global burden of disease, which estimates 14 million infection-related deaths annually, with 1.3 million attributed to antibiotic resistance. The antibiotic development era peaked in the 1930s–1960s, but recent failures in screening chemical libraries and high development costs have led to a decline in pharmaceutical interest. Despite scientific advancements in defining chemical properties to overcome Gram-negative pathogen permeation barriers, limited financial resources hinder progress. The Global Burden of Disease (GBD) reports emphasize the significance of antibiotic resistance, with 1.3 million deaths attributed to it in 2019. The GBD 2019 report identified the top diseases by age-standardized disability-adjusted life years (DALYs), showing that infectious diseases remain a major cause of death, particularly in children. The report also highlights the disparity in research funding for infectious diseases compared to HIV. The antibiotic resistance crisis is further exacerbated by geographical variations in mortality rates and the emergence of drug-resistant pathogens. The European and US perspectives reveal significant numbers of antibiotic-resistant infections and deaths, with the US reporting 2.9 million infections annually. The GBD 2019 report projects 10 million antibiotic-resistant deaths by 2050, underscoring the need for new antibiotics. The development of new antibiotics has faced challenges, including the limitations of the Waksman platform and synthetic chemistry approaches. Recent research has focused on exploring 'unculturable' bacteria, leading to the discovery of teixobactin and clovibactin, which show promise against Gram-positive pathogens. Physicochemical approaches to antibiotic permeation have been explored, with studies on E. coli and P. aeruginosa revealing key criteria for membrane permeability. Efflux pump inhibitors and synthetic antibiotics based on target structure data have also been developed, with compounds like arylomycin and cresomycin showing efficacy against resistant pathogens. The development of new antibiotics remains challenging due to scientific and economic barriers, but recent advances in modular synthesis and targeting bacterial outer membrane components offer promising avenues for future research.