Novel MscL agonists that allow multiple antibiotics cytoplasmic access activate the channel through a common binding site.

Robin Wray,Irene Iscla,Paul Blount,Junmei Wang,Peter J Bond

doi:10.1371/journal.pone.0228153

Abstract

The antibiotic resistance crisis is becoming dire, yet in the past several years few potential antibiotics or adjuvants with novel modes of action have been identified. The bacterial mechanosensitive channel of large conductance, MscL, found in the majority of bacterial species, including pathogens, normally functions as an emergency release valve, sensing membrane tension upon low-osmotic stress and discharging cytoplasmic solutes before cell lysis. Opening the huge ~30Å diameter pore of MscL inappropriately is detrimental to the cell, allowing solutes from and even passage of drugs into to cytoplasm. Thus, MscL is a potential novel drug target. However, there are no known natural agonists, and small compounds that modulate MscL activity are just now being identified. Here we describe a small compound, K05, that specifically modulates MscL activity and we compare results with those obtained for the recently characterized MscL agonist 011A. While the structure of K05 only vaguely resembles 011A, many of the findings, including the binding pocket, are similar. On the other hand, both in vivo and molecular dynamic simulations indicate that the two compounds modulate MscL activity in significantly different ways.

Highlights

Multi-drug resistance (MDR) in pathogenic bacteria is a major threat to human health
We characterize a new novel small-molecule compound that we coin as K05 that directly binds to and modulates MscL gating. We find that it has the characteristics anticipated for a MscL-specific agonist, including slowing bacterial growth of several bacterial species, increasing the potency of common antibiotics, and decreasing the viability of stationary cultures
The K05 compound was identified by an high throughput screen (HTS) designed to look for agonists to the MscL channel [19]

Summary

Introduction

Multi-drug resistance (MDR) in pathogenic bacteria is a major threat to human health. In 2013 the Centers for Disease Control (CDC) of US declared that the human race is in the “post-antibiotic era,” and in 2014, the World Health Organization (WHO) warned “the antibiotic resistance crisis is becoming dire” [1, 2]. Multidrug resistant bacteria have been declared a substantial threat to U.S public health and national security by the Infectious Diseases Society of America and the Institute of Medicine, as well as the federal Interagency Task Force on Antimicrobial Resistance. Two million Americans per year develop healthcare-associated infections, resulting in 99,000 deaths, most due to antibacterial resistant pathogens [1, 3].

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