The article discusses the global burden of disease caused by infection and the crisis of antibiotic resistance, highlighting the need for new antibiotics. It reviews the historical development of antibiotic discovery, from the golden age of 1930-1960 to the current challenges faced by the pharmaceutical industry. Despite scientific advancements in defining chemical properties needed to overcome the permeation barrier in Gram-negative pathogens and extending the chemical space of antibiotic candidates, the high cost and low return on investment have led to a decline in new antibiotic development. The article also examines the economic and strategic hurdles, such as the WHO's 'AWaRe' classification database, which further discourages investment in antibiotic research. Additionally, it explores innovative approaches to overcoming the outer membrane barrier, including the discovery of teixobactin and clovibactin, and the use of physicochemical approaches to enhance antibiotic permeation. The article concludes by discussing fully synthetic platforms using modular building blocks and the potential of targeting the bacterial outer membrane, such as murepavadin and darobactin, to develop new antibiotics.The article discusses the global burden of disease caused by infection and the crisis of antibiotic resistance, highlighting the need for new antibiotics. It reviews the historical development of antibiotic discovery, from the golden age of 1930-1960 to the current challenges faced by the pharmaceutical industry. Despite scientific advancements in defining chemical properties needed to overcome the permeation barrier in Gram-negative pathogens and extending the chemical space of antibiotic candidates, the high cost and low return on investment have led to a decline in new antibiotic development. The article also examines the economic and strategic hurdles, such as the WHO's 'AWaRe' classification database, which further discourages investment in antibiotic research. Additionally, it explores innovative approaches to overcoming the outer membrane barrier, including the discovery of teixobactin and clovibactin, and the use of physicochemical approaches to enhance antibiotic permeation. The article concludes by discussing fully synthetic platforms using modular building blocks and the potential of targeting the bacterial outer membrane, such as murepavadin and darobactin, to develop new antibiotics.