## 4 Poor PK Profiles but Safe for Humans  
The underlying antibacterial mechanism of delpazolid is similar to that of oxazolidinone in that it inhibits bacterial protein synthesis, which kills or inhibits the growth of bacteria [12]. However, protein synthesis also occurs in the mitochondria of eukaryotes, although mitochondria use independent protein-synthesis machinery that differs from nuclear-encoded protein synthesis in the cytoplasm. In humans, 13 genes are translated into proteins through this process, all of which participate in synthesizing membrane proteins associated with oxidative phosphorylation [13]. \begin{table}
\begin{tabular}{c l} \hline
**Clinical Trial Phase** & **Experimental Design and Adverse Effects Reported** \\ \hline \multirow{3}{*}{Phase 1a [9] (SAD)} & Study design: Double blind, randomized, placebo control, first-in-human design \\ \cline{2-3}  & N=64, 8 subject per group (6 active + 2 placebo) \\ \cline{2-3}  & Doses: 50, 100, 200, 400, 800, 1,600, 2,400, and 3,200 mg \\ \cline{2-3}  & **MTD: 2,400 mg (Up to 2,400 mg, only mild adverse events were reported)** \\ \hline \multirow{3}{*}{Phase 1b [8] (MAD-7 days)} & Study design: Double blind, randomized, placebo control \\ \cline{2-3}  & N=32, 8 subject per group (6 active + 2 placebo) \\ \cline{2-3}  & Doses: 400, 800, 1,200, 1,600 mg BID for 7 days \\ \cline{2-3}  & **MTD: 1,200 mg BID (Up to 2,400 mg/day, only mild adverse events were reported)** \\ \hline \multirow{3}{*}{Phase 1b [6] (MAD-21 days)} & Study design: Double blind, randomized, placebo control \\ \cline{2-3}  & N=36, 12 subject per group (10 active + 2 placebo) \\ \cline{2-3}  & Doses: 800 mg QD and BID, 1,200 mg BID for 21 days \\ \cline{2-3}  & **MTD: 1,200 mg BID (Up to 2,400 mg/day, No SAE reported)** \\ \hline \multirow{3}{*}{Phase 2a  \\ \cline{2-3}  & Results were not yet published. \\ \hline \end{tabular}
\end{table} 
Table 1: Summary of phase 1a/b and 2a dose-escalation study to assess the safety, tolerability, and pharmacokinetics of delpazolid as a single agent. However, oxazolidinones uniformly inhibit human mitochondrial protein synthesis [14]. Similarly, linezolid, an oxazolidinone analogue used to treat TB, inhibits mitochondrial protein synthesis with potentially severe clinical consequences [15]. Therefore, the inhibition of protein synthesis by oxazolidinone intended to kill bacteria can impair mitochondria inside eukaryotic cells. Furthermore, myelosuppression may be a product of linezolid inhibition of mitochondrial protein synthesis [16]. As shown in Table 2, delpazolid showed a greater inhibitory effect than linezolid towards _Escherichia coli_ at a 5-fold lower concentration (0.8 \(\mathrm{\SIUnitSymbolMicro g/mL}\)). In addition, in a study of human cells (immortalised myelogenous leukaemia cell line K562 and human cardiomyocyte cell line AC16), delpazolid showed inhibitory effects on mitochondrial protein synthesis similar to those of linezolid. Although delpazolid exhibited activity superior to that of linezolid in prokaryotic protein synthesis inhibition, it had similar negative effects on mitochondrial protein synthesis. Therefore, delpazolid doses lower than linezolid doses would be adequate for the treatment of Gram-positive bacteria, including TB. A lower dose would effectively inhibit bacterial protein synthesis, with relatively fewer adverse effects on human mitochondrial protein synthesis. The association between delpazolid and myelosuppression, one of the most serious side effects of linezolid, was also tested. Healthy subjects were administered delpazolid and linezolid, and the plasma area under the concentration-time curve (AUC) was determined. As shown in Figure 2, subjects were administered delpazolid at doses ranging from 400 to 1200 mg, and 600 mg linezolid as the comparator.