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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Development of Novel Immunoprophylactic Agents against Multidrug-Resistant Gram-Negative Bacterial Infections
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Development of Novel Immunoprophylactic Agents against Multidrug-Resistant Gram-Negative Bacterial Infections

机译：Development of Novel Immunoprophylactic Agents against Multidrug-Resistant Gram-Negative Bacterial Infections

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The widespread emergence of antibiotic resistance, including multidrug resistance in Gram-negative (G-) bacterial pathogens, poses a critical challenge to the current antimicrobial armamentarium. Antibody-drug conjugates (ADCs), primarily used in anticancer therapy, offer a promising treatment alternative due to their ability to deliver a therapeutic molecule while simultaneously activating the host immune response. The Cloudbreak platform is being used to develop ADCs to treat infectious diseases, composed of a therapeutic targeting moiety (TM) attached via a noncleavable linker to an effector moiety (EM) to treat infectious diseases. In this proof-of-concept study, 21 novel dimeric peptidic molecules (TMs) were evaluated for activity against a screening panel of G- pathogens. The activities of the TMs were not impacted by existing drug resistance. Potent TMs were conjugated to the Fc fragment of human IgGI (EM), resulting in 4 novel ADCs. These ADCs were evaluated for immunoprophylactic efficacy in a neutro-penic mouse model of deep thigh infection. In colistin-sensitive infections, 3 of the 4 ADCs offered protection similar to that of therapeutically dosed colistin, while CTC-171 offered enhanced protection. The efficacy of these ADCs was unchanged in colistin-re-sistant infections. Together, these results indicate that the ADCs used here are capable of potent binding to G- pathogens regardless of lipopolysaccharide (LPS) modifications that otherwise lead to antibiotic resistance and support further exploration of ADCs in the treatment of infections caused by drug-resistant G- bacteria.

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