In Vitro Activities of LCB 01-0648, a Novel Oxazolidinone, against Gram-Positive Bacteria

Abstract

Oxazolidinones are a novel class of synthetic antibacterial agents that inhibit bacterial protein synthesis. Here, we synthesized and tested a series of oxazolidinone compounds containing cyclic amidrazone. Among these compounds, we further investigated the antibacterial activities of LCB01-0648 against drug-susceptible or resistant Gram-positive cocci in comparison with those of six reference compounds. LCB01-0648 showed the most potent antimicrobial activities against clinically isolated Gram-positive bacteria. Against the methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCNS) isolates, LCB01-0648 showed the lowest MIC90s (0.5 mg/L) among the tested compounds. In addition, LCB01-0648 had the lowest minimum inhibitory concentrations (MICs) against the four linezolid-resistant S. aureus (LRSA) strains (range 2–4 mg/L). The results of the time–kill studies demonstrated that LCB01-0648 at a concentration 8× the (MIC) showed bactericidal activity against methicillin-susceptible Staphylococcus aureus MSSA or MRSA, but showed a bacteriostatic effect against LRSA. These results indicate that LCB01-0648 could be a good antibacterial candidate against multidrug-resistant (MDR) Gram-positive cocci.

In Vivo Activity of LCB 01-0699, a Prodrug of LCB 01-0648, against Staphylococcus aureus

“…Because LCB01-0699 showed less bone marrow toxicity ( Figure 4 ), LCB01-0699 is considered a potential antibacterial candidate, with high activities and low toxicity. While our previous study provided in vitro activities of LCB01-0648 against Linezolid -resistant S. aureus or other Gram-positive cocci [ 13 ], we did not provide in vivo activity of LCB01-0699 against Linezolid -resistant S. aureus or other Gram-positive cocci. Therefore, further in vivo analyses should be carried out to better understand the antibacterial activity of LCB01-0699 against multi-drug resistant Gram-positive cocci, including Linezolid -resistant S. aureus .…”

“…Previously, we reported that LCB01-0648 had potent in vitro activity and minimal safety issues [ 13 ]. To examine whether LCB01-0699 was really converted to LCB01-0648 in vivo, a pharmacokinetic study was conducted in a rat model system.…”

“…A myelosuppression assay was carried out as previously described [ 13 ]. Briefly, female C3H/HeJ (C3H) mice (6~7 weeks) were purchased from Orient Bio.…”

“…Previously, we reported on the antibacterial activities of a novel oxazolidinones LCB01-0648 , containing cyclic amidrazone [ 13 ]. LCB01-0648 showed potent antibacterial activities against clinically isolated Gram-positive cocci, suggesting that LCB01-0648 could be a good antibiotic candidate for treatment of infectious diseases caused by Gram-positive cocci [ 13 ]. While LCB01-0648 has potent antibacterial activities against multi-drug Gram-positive cocci in vitro, the in vivo activity of LCB01-0648 had not yet been examined.…”

Oxazolidinones as versatile scaffolds in medicinal chemistry

“…LegoChem Biosciences, Inc. (Daejeon, South Korea) has developed several oxazolidinone derivatives as antibacterial agents in the last decade. 32–35 For example, compound 13 (LCB01-0062) (Fig. 2) showed in vitro activity against clinical isolates of Gram-positive bacteria compared to several antibacterial drugs, including linezolid, erythromycin, ciprofloxacin, and vancomycin.…”