## 3 Results and Discussion
### Combinations of TPZs with Conventional Antibiotics
\begin{table}
\begin{tabular}{c c c c c c c c c c c c} \hline \hline \multirow{2}{*}{**Combination**} & \multicolumn{2}{c}{_E. coli_} & \multicolumn{2}{c}{_S. enterica_} & \multicolumn{2}{c}{_S. aureus_} & \multicolumn{2}{c}{_S. enterica_} \\  & \multicolumn{2}{c}{**ATCC 25922**} & \multicolumn{2}{c}{**SL 5676**} & \multicolumn{2}{c}{**ATCC 25923**} & \multicolumn{2}{c}{**AcrAB-TolCIC**} \\ \cline{2-11}  & \begin{tabular}{c} **MIC** \\ **(mg/mL)** \\ \end{tabular} & **FP** & **FICI** & \begin{tabular}{c} **MIC** \\ **(mg/mL)** \\ \end{tabular} & **FP** & **FICI** & \
\begin{tabular}{c} **MIC** \\ **(mg/mL)** \\ \end{tabular} & **FP** & **FICI** &
\begin{tabular}{c} **MIC** \\ **(mg/mL)** \\ \end{tabular} & **FP** & **FICI** \\ \hline TPZ(1)/Cipro(1/4 MIC) & 4.0 & 2 & 0.75 & 4.0 & 2 & 0.75 & 8.0 & 2 & 0.75 & 8.0 & 1 & 1.25 \\ TPZ(1)/Cipro(1/2 MIC) & **0.5** & **16** & **0.56** & 1.0 & 8 & 0.62 & 2.0 & 8 & 0.63 & 8.0 & 1 & 1.50 \\ \hline TPZ (1)/NFT(1/4 MIC) & 4.0 & 2 & 0.75 & 4.0 & 2 & 0.75 & **4.0** & **4** & **0.50** & 8.0 & 1 & 1.25 \\ TPZ (1)/NFT(1/2 MIC) & **0.13** & **62** & **0.52** & **0.03** & **267** & **0.50** & **1.0** & **16** & **0.56** & 8.0 & 1 & 1.50 \\ \hline (2)/Cipro (1/4 MIC) & 0.13 & 2 & 0.77 & 0.13 & 2 & 0.75 & 0.25 & 2 & 0.75 & 0.25 & 1 & 1.25 \\ (2)/Cipro(1/2 MIC) & 0.06 & 4 & 0.77 & 0.06 & 4 & 0.75 & 0.06 & 8 & 0.62 & 0.13 & 2 & 1.00 \\ \hline (2)/NFT(1/4 MIC) & 0.13 & 2 & 0.77 & 0.13 & 2 & 0.77 & **0.13** & **4** & **0.50** & 0.25 & 1 & 1.50 \\ (2)/NFT(1/2 MIC) & **0.015** & **17** & **0.56** & **0.0075** & **36** & **0.53** & 0.06 & 8 & 0.62 & 0.13 & 2 & 1.00 \\ \hline \hline \end{tabular}
\end{table} 
Table 3: The minimum inhibitory concentration (MIC), the fold potentiation (FP) and the fractional inhibitory concentration index (FICI) of TPZ drug (**1**) and its most potent derivative (compound **2**) in combinations with sub-inhibitory concentrations of conventional antibiotics ciprofloxacin (Cipro) and nitrofurantoin (NFT). The strongest combined effects are indicated in bold. Weak partial synergistic and virtually additive effects (FICI \(\sim\)0.75-0.77) were defined for the tested compounds by varying their concentrations in the presence of the fixed 1/4 MIC concentrations of Cipro and NFT against the representative Gram-negative and -positive strains, with a two-fold reduction in the MICs of the compounds (note the exception revealed in combinations of TPZs with NFT against the _S. enterica_ strain, which resulted in a four-fold reduction in the MICs of di-\(N\)-oxides (suggestive of complete synergistic effect, FICI \(\sim\) 0.5 (Table 3); Figure 2C3,D3). The markedly greater partial synergistic and virtually complete synergistic effects (with FICI of \(\sim\)0.56-0.50) were defined for the combined actions of TPZs with the 1/2 MIC concentrations of antibiotics against Gram-negative strains. The strongest combined effects were achieved for the inhibitory potencies of the compounds coupled with the NFT drug, with an approximately 270-fold and 62-fold reduction in the MICs of TPZ (**1**) against the _S. enterica_ strain (FICI \(\sim\) 0.50; Figure 2C2) and _E.coli_ (FICI = 0.52; Figure 2C1), and followed by a 36- and 17-fold decrease in the MICs of the lead  
Figure 2: Isobolograms of combinations of TPZ (**1**) and the lead compound **2**_versus_ ciprofloxacin and nitrofurantoin expressed in terms of their fractional inhibition concentration (FIC) values against Gram-negative _E. coli_ (**A1–D1**) and _S. enterica_ (**A2–D2**) strains, the Gram-positive _S. aureus_ strain (**A3–D3**), and the _S. enterica_ strain over-expressing AcrAB-TolC (**A4–D4**). The straight lines connecting the end points of the y- and x-axis of the FICs of TPZs and antibiotics, respectively, represent total synergistic effect (dot-dashed line), partial synergistic (dashed line) and additive (non-interactive) effect (solid line). All experiments were performed in triplicate on at least two different occasions. compound (**2**) against the _S. enterica_ (FICI = 0.53, Figure 2D2) and _E.