Design and evaluation of a bifunctional fusion polypeptide for targeted delivery of tigecycline against drug-resistant Klebsiella pneumoniae

The overuse of antibiotics and the continuous evolution of drug-resistant bacteria present substantial obstacles to the clinical treatment of Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. This study reports the rational design of a bifunctional fusion polypeptide, S-thanatin (Ts)-functionalized elastin-like carrier (Ts-ELP), which integrates the antimicrobial peptide (AMP) Ts with a human-derived elastin‑like polypeptides (ELPs). This designer polypeptide serves as a smart carrier, capable of efficiently encapsulating the broad-spectrum antibiotic tigecycline (Tig) via reversible temperature-responsive phase transition hydrophobic interaction, resulting in a self-assembled, targeted nano-antibiotic, Tig@Ts-ELP (Tig@TsE). Comprehensive in vitro and in vivo evaluations demonstrate that Tig@TsE exhibits multiple advantageous features, including rapid and simple preparation, specific lipopolysaccharide (LPS)-targeting capability, excellent in vivo targeted delivery efficiency, and dual-responsive drug release triggered by the acidic pH and elevated matrix metalloproteinase-9 (MMP-9) levels in the CRKP-infected microenvironment, coupled with favorable biocompatibility. Moreover, the Ts peptide and Tig exhibit marked synergistic antibacterial effects against CRKP. This innovative nano-antibiotic delivery system is designed to increase local drug concentration at the infection site, boost bactericidal activity, and reduce systemic toxicity, thereby presenting a promising therapeutic strategy for the treatment of drug-resistant bacterial pneumonia.