In Silico Optimization of a <i>Streptomyces</i> sp. Antimicrobial Peptide Against Oncobacteria in Oral Squamous Cell Carcinoma

ABSTRACT Oral squamous cell carcinoma (OSCC) is a major public health concern, accounting for more than 90% of all oral malignancies. Pathogenic bacteria, such as Streptococcus mutans , Fusobacterium nucleatum , and Porphyromonas gingivalis , are closely linked to OSCC and promote chronic inflammation, a key factor in the tumor microenvironment. The increasing incidence of oral malignancies necessitates the development of antimicrobial peptides (AMPs) with enhanced anticancer activity as targeted therapeutics against bacteria to mitigate their impact on OSCC. A total of 182 Streptomyces genus‐derived AMPs were collected and analyzed in silico to determine their potent antibacterial and anticancer characteristics. Fourteen AMPs were tested for 3D structural alignment prediction and validation, and the most efficient peptide was determined to be sAMP2. A genome‐based analysis of the peptide sourced from Streptomyces globisporus C‐1027 was conducted to explore its evolutionary significance. The cell‐penetrating peptide activity of sAMP2 was optimized to make it more stable and better able to target OSCC host cellular receptors. The peptide Mut_sAMP2 was found to interact with the bacterial virulence proteins DEX of S. mutans , LPS of F. nucleatum , and KGP of P. gingivalis and with OSCC‐associated proteins (TNFα, IL‐6, IL‐8, p38, p53, E‐cadherin, Jak‐1, and PAR2) with greater binding affinity. The peptide Mut_sAMP2 treated OECM‐1 cells showed reduced cell survival by the cytotoxicity activity of IC50 5.4 μg/mL. To the best of our knowledge, our computational study is the first to significantly impact the development of new and effective cancer therapeutics from Streptomyces sp. derived AMPs with a broad spectrum of activity and potential evaluating to combat OSCC progression linked with oral oncobacteria.