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KKL-35 is a new oxadiazole compound with potent broad-spectrum antibacterial activity against a number of gram-positive and gram-negative bacteria. However, its influences on bacterial growth are unclear. This study is to investigate phenotypic changes of Staphylococcus aureus (SA) caused by KKL-35 and evaluate antibacterial activity of combinations of KKL-35 with 7 class of antibiotics available in medical facilities. KKL-35-treated SA showed significantly lower survival under stresses of NaCl and H 2 O 2 than DMSO (21.03 ± 2.60% vs. 68.21 ± 5.31% for NaCl, 4.91 ± 3.14% vs. 74.78 ± 2.88% for H 2 O 2 ). UV exposure significantly decreased survival of SA treated with KKL-35 than DMSO-treated ones (23.91 ± 0.71% vs. 55.45 ± 4.70% for 4.2 J/m 2 , 12.80 ± 1.03% vs. 31.99 ± 5.99% for 7.0 J/m 2 , 1.52 ± 0.63% vs. 6.49 ± 0.51% for 14.0 J/m 2 ). KKL-35 significantly decreased biofilm formation (0.47 ± 0.12 vs. 1.45 ± 0.21) and bacterial survival in the serum resistance assay (42.27 ± 2.77% vs. 78.31 ± 5.64%) than DMSO. KKL-35 significantly decreased ethidium bromide uptake and efflux, as well as the cell membrane integrity. KKL-35 had low cytotoxicity and low propensity for resistance. KKL-35 inhibited SA growth in concentration-independent and time-dependent manners, and showed additivity when combined with the majority class of available antibiotics. Antibiotic combinations of KKL-35 with ciprofloxacin, rifampicin, or linezolid significantly decreased bacterial loads than the most active antibiotic in the corresponding combination. Thus, KKL-35 inhibits growth of SA by decreasing bacterial environmental adaptations, biofilm formation, membrane uptake and efflux, as well as increasing antibiotic sensitivity. Its potent antibacterial activity, low cytotoxicity, low propensity for resistance, and wide choices in antibiotic combinations make KKL-35 a promising leading compound to design new antibiotics in monotherapies and combination therapies to treat bacterial infections., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)