Venturicidin A, A Membrane-active Natural Product Inhibitor of ATP synthase Potentiates Aminoglycoside Antibiotics

Venkateswarlu Yarlagadda,Gerard D Wright,Ricardo Medina

doi:10.1038/s41598-020-64756-0

Venkateswarlu Yarlagadda, Gerard D Wright + Show 1 more

Open Access

https://doi.org/10.1038/s41598-020-64756-0

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Abstract

Despite the remarkable advances due to the discovery and development of antimicrobials agents, infectious diseases remain the second leading cause of death worldwide. This fact underlines the importance of developing new therapeutic strategies to address the widespread antibiotic resistance, which is the major contributing factor for clinical failures of the current therapeutics. In a screen for antibiotic adjuvants, we identified a natural product from actinomycetes, venturicidin A (VentA), that potentiates the aminoglycoside antibiotic gentamicin against multidrug-resistant clinical isolates of Staphylococcus, Enterococcus, and Pseudomonas aeruginosa. Furthermore, the combination of gentamicin and VentA was bactericidal and rapidly eradicated methicillin-resistant S. aureus (MRSA). The molecular mechanism of gentamicin potentiation activity is attributed to uncoupling of ATP synthesis by VentA from electron transport presumably by blocking the proton flow through ATP synthase, which results in an elevated concentration of extracellular protons and subsequent anticipated raise in gentamicin uptake. The disruption of the proton flux was characterized by perturbed membrane potential in MRSA. These results demonstrate that inhibition of ATP synthase along with the subsequent membrane dysregulation, as shown here with VentA, complements aminoglycoside antibiotics against MDR bacteria, and that this approach may be employed to combat bacterial resistance.

Highlights

Multidrug resistance is common in most bacterial pathogens[1]
We screened a library of actinomycetes extracts for the ability to rescue the activity of gentamicin against gentamicin-resistant methicillin-resistant S. aureus (MRSA) that harbors a bifunctional aminoglycoside-modifying enzymes (AMEs), AAC(6′)-Ie-APH(2′′)-Ia
The antifungal mechanism of venturicidin A (VentA) was explored in the 1980s identifying it as an inhibitor of ATP synthase that acts by blocking the proton channel[28,29]

Summary

Introduction

Multidrug resistance is common in most bacterial pathogens[1]. Even so-called last resort drugs such as polymyxins, oxazolidinones, and carbapenems are increasingly inactive against many clinical, and sometime epidemic, strains[1,2,3,4,5]. One potential solution to the antibiotic crisis is the use of combinations of antibiotics, and antibiotic adjuvants[8] The former are well established for the treatment of antibiotic tolerant bacterial pathogens such as enterococci and mycobacteria[9] while the latter offer several strategies to enhance the activity of our existing antibiotic drugs, even against highly resistant strains[10]. Aminoglycosides were among the first antibiotics clinically deployed having broad coverage of bacterial spectrum and bactericidal activity[11] They target the 30S ribosomal subunit, resulting in disruption of mRNA decoding with subsequent production of aberrant proteins[12,13]. We screened for gentamicin rescue in an aminoglycoside resistant MRSA strain and identified venturicidin A (VentA) produced by a soil-isolated actinomycetes, WAC 9126, as an aminoglycoside adjuvant

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