aureus can develop resistance to any antibiotic. As seen in the old derivation of mecA in the history of life on the earth, antibiotic resistance is the natural consequence of the production of antibiotics. Based on this principle, we should design a new chemotherapeutic strategy. The bacteria of our time is drastically changed as compared to that of the 1940s, when more than half of the hospital-associated S. aureus is methicillin-resistant, and more than 80% VISA are quinolone-resistant [59]. Given this, it is much more promising to develop an antibiotic that

has stronger activity against the S. aureus strains resistant to extant antibiotics rather than against wild-type S. aureus strains which are still susceptible to them. If such anti-resistance Dinaciclib nmr antibiotics were used in combination with the extant antibiotics, most of the S. aureus infections would become

treatable. By screening 1928 culture supernatants of Actinobacteria, we identified a curious substance that possessed a strong bactericidal activity against fluoroquinolone-resistant VISA strain Mu50, whereas only a weak activity against fluoroquinolon-, and methicillin-susceptible VSSA strain FDA209P [59]. The substance was found out to be an old antibiotic Nybomycin (NYB) that had been reported in 1955 [60]. We found that NYB strongly inhibited the function of the mutated DNA gyrase of CDK inhibitors in clinical trials quinolone-resistant Mu50, but did not inhibit the function of the wild-type DNA gyrase of quinolone-susceptible S. aureus [59]. Docking simulation study revealed stable binding of NYB to the quinolone-binding pocket of the GyrA having gyrA(S84L) mutation ( Fig. 6). On the other

hand, fluoroquinolone antibiotics cannot bind to it due to the mutational loss of the Serine residue, which is important to retain hydrogen-bond network for the stabilization of quinolone molecule in the quinolone-binding pocket ( Fig. 6). Bacteria always find the way to develop resistance to any antibiotic. As is expected, NYB was not exempt from the emergence of resistance, either. Mu50 did generate NYB-resistant mutants (temporarily defined by MIC ≥ 4 mg/L), although at extremely low frequencies: the unless appearance rates were 0.663–15.3 × 10−11[59]. However, surprisingly, all of the nine independently obtained resistant mutant strains were susceptible to fluoroquinolone antibiotics [59]. Nucleotide sequencing revealed that their gyrA genes of the resistant mutants were back mutated to the wild type. Therefore the resistant mutants were genetic revertants [59]. Accordingly, we designated NYB as a ‘Reverse Antibiotic’ (RA) against quinolone-resistant bacteria [59]. Recently, we found that some of the flavones as well are RAs against fluoroquinolone-resistant bacteria (Morimoto, Y. et al. in preparation). Flavones are known as natural antibiotics produced by plants [61]. NYB is also a natural antibiotic.