Test Your Hypothesis

 BGPT Odds of True

hPepT2-uptake reduction for FADDI-795 is directly reported with retained MICs and no nephrotoxicity; lipid A binding preservation is only inferred from MICs, and nephrotoxicity n=3/group widens uncertainty.

 Hypothesis Novelty

First explicit structure-interaction map of polymyxin Dab residues with hPepT2, and among the first demonstrations that a single-Dab substitution can decouple antibacterial activity from renal uptake.

 Quick Analysis Plan Copied

 Long Analysis Plan

Verdict: Evidence supports hPepT2-specific reduction; lipid A binding is inferred only indirectly

The 2026 hPepT2 structure-interaction study directly tested this question. In uptake assays in hPepT2-overexpressing HEK293 cells, FADDI-795 (Dab3→Ala) showed reduced hPepT2-mediated uptake, whereas the Dab8-mutant FADDI-167 did not—narrowing the interaction-competent Dab positions to Dab1, Dab3, Dab5, and Dab9 Dab-residue uptake comparison.

The functional consequences split cleanly: FADDI-795 was the most active analogue, with MICs comparable to polymyxin B against most tested strains (except FADDI-PA025), and showed no observable nephrotoxicity in the mouse model (n=3/group), unlike the other three analogues FADDI-795 MIC and nephrotoxicity data. Retained MICs are consistent with preserved LPS/lipid A–directed killing, but no direct lipid A binding measurement (e.g., ITC, dansyl-polymyxin displacement, LPS-binding assay) is reported—this arm of the hypothesis is inferred, not demonstrated.

MD simulations placed polymyxin B at the hPepT2 lateral opening site, with Dab1/Dab8/Dab9 electrostatic interaction energies of −180 to −260 kJ/mol and Dab3/Dab5 noted as probable contributors; hPepT2 D215A roughly doubled apparent K_m for the polymyxin probe MIPS-9541 (p=0.033) MD binding energetics and D215A kinetics.

Blind spots

• Nephrotoxicity cohort was only 3 mice/group (proof-of-concept); no pharmacokinetic or renal-accumulation data exist for FADDI-795.
• No direct lipid A binding assay; MIC retention is an indirect proxy.
• MD did not capture full translocation; reduced uptake could reflect altered binding, translocation, or both.

Plot of the reported binary uptake outcome for each Dab→Ala analogue; exact fold-changes were not reported numerically. Reduced uptake plus retained MICs and absent nephrotoxicity is the pattern expected for selective hPepT2 disruption.