Abstract
Gram-negative bacteria are uniquely equipped to defeat antibiotics. Their outermost layer, the cell envelope, is a natural permeability barrier that contains an array of resistance proteins capable of neutralizing most existing antimicrobials. As a result, its presence creates a major obstacle for the treatment of resistant infections and for the development of new antibiotics. Despite this seemingly impenetrable armor, in-depth understanding of the cell envelope, including structural, functional and systems biology insights, has promoted efforts to target it that can ultimately lead to the generation of new antibacterial therapies. In this article, we broadly overview the biology of the cell envelope and highlight attempts and successes in generating inhibitors that impair its function or biogenesis. We argue that the very structure that has hampered antibiotic discovery for decades has untapped potential for the design of novel next-generation therapeutics against bacterial pathogens.