Multidrug-resistant (MDR) bacteria pose a serious threat to global health, requiring new classes of antimicrobial agents. This study presents the development of α-helical antimicrobial peptides (AMPs) as nanoscale molecular tools, designed through a structure-based approach guided by the Main Mechanical Forces (MMFs) method. Amphipathic helical conformations can be predicted and stabilized using MMF-guided design, improving membrane interaction and antimicrobial effectiveness. Starting from the MMF-predicted structure of peptide HT2, amphipathic peptides were designed by aligning hydrophobic and cationic residues on opposite helix faces to target and disrupt bacterial membranes. Three analogues were developed: K1 (Arg1→Lys), K1-4-5 (Arg1/4/5→Lys), and K1-4-5-A, a covalently modified version of K1-4-5 bearing allomaltol as a terminal metal-chelating group. All peptides were synthesized via Fmoc-based solid-phase peptide synthesis, and FT-IR was used to confirm their structural integrity. The structures were also confirmed by ESI+ MS and elemental analysis. The antimicrobial efficacy was assessed against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae, tested both with the individual peptides and in combination with allomaltol to explore potential synergistic effects. HT2 exhibited strong activity against S. aureus (MIC = 18.75 μM), moderate activity against E. coli (75 μM), and limited efficacy against K. pneumoniae (150 μM). In contrast, K1 was inactive (MIC > 300 μM), highlighting the importance of the Arg1 guanidinium group. K1-4-5 retained partial activity, and its co-administration with allomaltol significantly improved MIC values against S. aureus and E. coli (37.5 μM), suggesting a synergistic effect. Notably, the modified peptide K1-4-5-A restored full activity against S. aureus (MIC = 18.75 μM), comparable to HT2. This work demonstrates how MMF-guided design enables the development of structurally optimized AMPs with dual antimicrobial mechanisms. The combination of membrane-disruptive properties and metal ion chelation offers a promising nanoscale strategy to fight MDR bacteria and develop next-generation nanomaterial-based therapeutics.