Bacterial leaf spot (BLS) is a disease of tomatoes caused by Xanthomonas gardneri (Xg), X. perforans (Xp), X. vesicatoria (Xv) and X. euvesicatoria (Xev). BLS leads to tremendous losses to the tomato industry and is difficult to manage due to epiphytic survival of Xanthomonas, emergence of copper and streptomycin resistant strains, lack of resistant tomato cultivars and effective bactericides against Xanthomonas. Objective of this study was to identify novel small molecule (SM) growth inhibitors against Xanthomonas spp. Total 17 out of 4,182 SMs completely inhibited the growth of Xg, Xp, Xv and Xev at 100 micromolar. Of these, 8 SMs were effective against other BLS isolates (n=119), including copper and streptomycin resistant isolates. These SMs had minimal impact on plant pathogenic (n=22) and beneficial bacteria (n=12) and displayed no toxicity on tomato plant tissues. Electron micrography suggested that SMs treatment disrupted the cell membrane of Xanthomonas. Further, these SMs reduced Xg population in infested seeds (up to 1.5 log) and infected seedlings (up to 3.5 log CFU/plant; P value less than 0.05) when used as a curative treatment at 200 and 500 micromolar of SMs, respectively. Similar trend was observed after real-time bioluminescent imaging of plants infected with engineered bioluminescent Xg (BL-Xg) after treatment with SMs (P value less than 0.05). In summary, we have identified 8 novel SMs showing antimicrobial activity against BLS of tomato and our ongoing studies are focused on testing against other Xanthomonas spp., and in naturally infected seeds.