Antimicrobial drug resistance is a growing threat to global public health. 
Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus 
faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, 
Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because 
they are responsible for many serious infections in hospitals. Although some 
promising agents are in the pipeline, there is an urgent need for new antibiotic 
scaffolds. However, antibacterial researchers have struggled to identify new 
small molecules with meaningful cellular activity, especially those effective 
against multidrug-resistant Gram-negative pathogens. This difficulty ultimately 
stems from an incomplete understanding of efflux systems and compound permeation 
through bacterial membranes. This Opinion article describes findings from 
target-based and phenotypic screening efforts carried out at AstraZeneca over 
the past decade, discusses some of the subsequent chemistry challenges and 
concludes with a description of new approaches comprising a combination of 
computational modelling and advanced biological tools which may pave the way 
towards the discovery of new antibacterial agents.