“…Although no antibiotics discovered through HTS methods have made it to the clinics so far, recent improvements in the antibiotic discovery pipeline have resulted in promising new therapeutic leads (4). A combination of HTS with rational design Abbreviations: CuAAC, copper (I)-catalyzed azide-alkyne cycloaddition; MoA(s), mechanism(s) of action; HTS, high-throughput screening; FDA, Food and Drug Administration; BamA, component A of the b-barrel assembly machinery complex; DBO, diazabicyclooctane; SPRR, structure-porin permeation relationships; ESKAPE, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species; JNK, c-Jun N-terminal kinase; NRP(s), non-ribosomal peptide(s); antiSMASH, antibiotics and secondary metabolite analysis shell; BGC(s), biosynthetic gene cluster(s) (BGC); NRPS(s), non-ribosomal peptide synthetase(s); NMR, nuclear magnetic resonance; IC 50 , half maximal inhibitory concentration; ABP(s), activity-based probe(s); ABPP, activity-based probe profiling; PG, peptidoglycans; LPS, lipopolysaccharides; CPS, capsular polysaccharides; VRSA, vancomycin-resistant S. aureus; VSSA, vancomycinsensitive S. aureus; SA, staphyloferrin A; BONCAT, bioorthogonal noncanonical amino acid tagging; DiZPK, ((3-(3-methyl-3H-diazirin-3-yl)propamino) carbonyl)-N ϵ -L -lysine; ACPK, N ϵ -((((1R,2R)-2-azidocyclopentyl)oxy)carbonyl)-holds great promise in producing new scaffolds to overcome resistance and expand pathogen scope given the advances in synthetic chemistry and an increased knowledge on the desired pharmacokinetic properties of antibiotics (3,14,15). Moreover, a switch from reductionist genes-to-drugs studies to more comprehensive systems-level approaches in antibacterial drug discovery has proven fundamental to identify antibiotics with novel MoAs and less prone to resistance (3).…”