Reprogrammed SimCells for antimicrobial therapy
Abstract
Antimicrobial resistance (AMR) is a critical global health challenge. In this study, we developed a platform based on chromosome-free and nonreplicating simple cells (SimCells, size 1 to 2 µm) and mini-SimCells (size 100 to 400 nm) for targeted pathogen elimination. Engineered with surface-displayed nanobodies, SimCells and mini-SimCells selectively bind bacteria expressing specific antigens (e.g., OmpA in Escherichia coli). The selective interactions facilitate close SimCell-pathogen proximity, enabling two antimicrobial mechanisms: direct injection of toxic effectors into bacterial cytoplasm via a heterologous expression of type VI secretion system (T6SS), and enzymatic conversion of aspirin into catechol by engineered salicylate hydroxylase, leading to sustained local production of hydrogen peroxide (H2O2). Our results demonstrate that both reprogrammed SimCells and mini-SimCells can eliminate target E. coli with high specificity and efficiency. Multidose reprogrammed mini-SimCell treatment led to a 103-fold selective reduction of targeted bacteria in mixed microbial communities, with minimal disruption to nontarget bacteria. We demonstrate that reprogrammed mini-SimCells, engineered with nanobody targeting outer membrane protein OmpA of the clinically relevant multidrug-resistant pathogen E. coli ST131, achieved elimination efficiencies over 97% at 24 and 48 h. This modularized "plug-and-play" antimicrobial platform provides a highly specific, efficient, and adaptable…
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