Composition and method for new antimicrobial agents with secondary mode of action

Abstract

Antibiotic agents conjugated to a guanidinium-rich molecular transporter (GR-MoTr) are provided. The drug conjugates show surprising increases in efficacy compared to the unconjugated drug in difficult-to-treat bacterial infections including biofilms, stationary and persister cells, and multi-drug resistant bacteria, as well as intracellular bacteria.

Description

[0001] cross reference [0002] This patent application claims priority to U.S. Provisional Patent Application No. 62 / 633,368, filed February 21, 2018, which is hereby incorporated by reference in its entirety. Background technique [0003] Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of death from antibiotic-resistant infections in the United States, accounting for an estimated 50% of all hospital-acquired / associated infections in Asia, North and South America %above. MRSA manifests primarily as skin and soft tissue infections (SSTIs), and if left untreated, MRSA infections can be transmitted hematogenously, leading to life-threatening illness. The propensity of MRSA to form biofilms and persist cells is associated with recurrent infections and chronic disease. Biofilms consist of slow-growing bacterial cells enclosed in a self-produced extracellular matrix, whereas persisters are dormant, highly antibiotic-resistant cells that exist in a plankton...

AI Technical Summary

Problems solved by technology

In addition to being unable to treat resistant pathogens with D-Ala-D-Lac termini, vancomycin can only exert its efficacy against actively growing bacteria with expanding cell walls

Therefore, vancomycin cannot clear infected cells consisting of slowly growing cells, for example, those containing biofilms or persisters

This ineffectiveness can lead to chronic infection, in which surviving slow-growing bacteria switch to an actively growing state and spread to previously uncolonized niches

In addition, vancomycin has a poor ability to penetrate mammalian cells, thus allowing pathogens such as MRSA to invade and persist in cells to avoid the effects of vancomycin treatment

Finally, vancomycin exhibits a relatively slow bactericidal mode of action against infectious agents, resulting in inefficient clearance of infection and, in some cases, clinical failure

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