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<i>Lysobacter</i> species are a group of environmental bacteria that are emerging as a new source of antibiotics. One characteristic of <i>Lysobacter</i> is intrinsic resistance to multiple antibiotics, which had not been studied. To understand the resistance mechanism, we tested the effect of blocking two-component regulatory systems (TCSs) on the antibiotic resistance of <i>Lysobacter enzymogenes</i>, a prolific producer of antibiotics. Upon treatment with LED209, an inhibitor of the widespread TCS QseC/QseB, <i>L. enzymogenes</i> produced a large amount of an unknown metabolite that was barely detectable in the untreated culture. Subsequent structural elucidation by nuclear magnetic resonance (NMR) unexpectedly revealed that the metabolite was indole. Indole production was also markedly induced by adrenaline, a known modulator of QseC/QseB. Next, we identified two TCS genes, <i>L. enzymogenes</i><i>qseC</i> (<i>Le-qseC</i>) and <i>Le-qseB</i>, in <i>L. enzymogenes</i> and found that mutations of <i>Le-qseC</i> and <i>Le-qseB</i> also led to a dramatic increase in indole production. We then chemically synthesized a fluorescent indole probe that could label the cells. While the <i>Le-qseB</i> (cytoplasmic response regulator) mutant was clearly labeled by the probe, the <i>Le-qseC</i> (membrane sensor) mutant was not labeled. It was reported previously that indole can enhance antibiotic resistance in bacteria. Therefore, we tested if the dramatic increase in the level of indole production in <i>L. enzymogenes</i> upon blocking of <i>Le-qseC</i> and <i>Le-qseB</i> would lead to enhanced antibiotic resistance. Surprisingly, we found that indole caused the intrinsically multiantibiotic-resistant bacterium <i>L. enzymogenes</i> to become susceptible. Point mutations at conserved amino acids in <i>Le</i>-QseC also led to antibiotic susceptibility. Because indole is known as an interspecies signal, these findings may have implications.<b>IMPORTANCE</b> The environmental bacterium <i>Lysobacter</i> is a new source of antibiotic compounds and exhibits intrinsic antibiotic resistance. Here, we found that the inactivation of a two-component regulatory system (TCS) by an inhibitor or by gene deletion led to a remarkable increase in the level of production of a metabolite in <i>L. enzymogenes</i>, and this metabolite was identified to be indole. We chemically synthesized a fluorescent indole probe and found that it could label the wild type and a mutant of the TCS cytoplasmic response regulator but not a mutant of the TCS membrane sensor. Indole treatment caused the intrinsically multidrug-resistant bacterium <i>L. enzymogenes</i> to be susceptible to antibiotics. Mutations of the TCS sensor also led to antibiotic susceptibility. Because indole is known as an interspecies signal between gut microbiota and mammalian hosts, the observation that indole could render intrinsically resistant <i>L. enzymogenes</i> susceptible to common antibiotics may have implications.