Title: Synthetic ionophores as non-resistant antibiotic adjuvants
Antimicrobial resistance is a world-wide health care crisis. New antimicrobials must both exhibit potency and thwart the ability of bacteria to develop resistance to them. We report the use of synthetic ionophores as a new approach to developing non-resistant antimicrobials and adjuvants. Most studies involving amphiphilic antimicrobials have focused on either developing synthetic amphiphiles that show ion transport, or developing non-cytotoxic analogs of such peptidic amphiphiles as colistin. We have rationally designed, prepared, and evaluated crown ether-based synthetic ionophores (‘hydraphiles’) that show selective ion transport through bilayer membranes and are toxic to bacteria. We report here that hydraphiles exhibit a broad range of antimicrobial properties and that they function as adjuvants in concert with FDA-approved antibiotics against multi-drug resistant (MDR) bacteria. Studies described herein demonstrate that benzyl C 14 hydraphile (BC 14 H) shows high efficacy as an antimicrobial. BC 14 H, at sub-MIC concentrations, forms aggregates of ∼200 nm that interact with the surface of bacteria. Surface-active BC 14 H then localizes in the bacterial membranes, which increases their permeability. As a result, antibiotic influx into the bacterial cytosol increases in the presence of BC n Hs. Efflux pump inhibition and accumulation of substrate was also observed, likely due to disruption of the cation gradient. As a result, BC 14 H recovers the activity of norfloxacin by 128-fold against resistant Staphylococcus aureus . BC 14 H shows extremely low resistance development and is less cytotoxic than colistin. Overall, synthetic ionophores represent a new scaffold for developing efficient and non-resistant antimicrobial-adjuvants. more »« less
As we are on the cusp of the “post-antibiotic” era due to rapid spread of drug resistant bacteria, there is an urgent need for new antimicrobials that are not susceptible to bacterial resistance mechanisms. In this review, we will discuss the recent development of “polymer therapeutics” with antimicrobial activity. Learning from host-defence peptides, we propose the biomimetic design of synthetic polymers to target bacterial cell membranes, which act by compromising the membrane integrity. The discussion is extended to the future challenges and opportunities of antimicrobial polymers for clinical applications.
The threat of antibiotic resistance warrants the discovery of agents with novel antimicrobial mechanisms. Antimicrobial peptides (AMPs) directly disrupting bacterial membranes may overcome resistance to traditional antibiotics. AMP development for clinical use has been mostly limited to topical application to date. We developed a rational framework for systematically addressing this challenge using libraries composed of 86 novel Trp- and Arg-rich engineered peptides tested against clinical strains of the most common multidrug-resistant bacteria known as ESKAPE pathogens. Structure-function correlations revealed minimum lengths (as low as 16 residues) and Trp positioning for maximum antibacterial potency with mean minimum inhibitory concentration (MIC) of 2–4 μM and corresponding negligible toxicity to mammalian cells. Twelve peptides were selected based on broad-spectrum activity against both gram-negative and -positive bacteria and <25% toxicity to mammalian cells at maximum test concentrations. Most of the selected PAX remained active against the colistin-resistant clinical strains. Of the selected peptides, the shortest (the 16-residue E35) was further investigated for antibacterial mechanism and proof-of-concept in vivo efficacy. E35 killed an extensively-resistant isolate of Pseudomonas aeruginosa (PA239 from the CDC, also resistant to colistin) by irreversibly disrupting the cell membranes as shown by propidium iodide incorporation, using flow cytometry and live cell imaging. As proof of concept, in vivo toxicity studies showed that mice tolerated a systemic dose of up to 30 mg/kg peptide and were protected with a single 5 mg/kg intravenous (IV) dose against an otherwise lethal intraperitoneal injection of PA239. Efficacy was also demonstrated in an immune-compromised Klebsiella pneumoniae infection model using a daily dose of 4mg/kg E35 systemically for 2 days. This framework defines the determinants of efficacy of helical AMPs composed of only cationic and hydrophobic amino acids and provides a path for a potential departure from the restriction to topical use of AMPs toward systemic application.
Patel, Mohit B.; Meisel, Joseph W.; Negin, Saeedeh; Gokel, Michael R.; Garrad, Evan; Gokel, George W.(
, Annals of pharmacology and pharmaceutics)
null
(Ed.)
Hydraphiles are synthetic amphiphiles that form pores in bilayer membranes. A study was undertaken to determine if the formation of pores could assist the penetration of antibiotics into bacteria. The disruption of ion homeostasis by the pore-formers leads to microbial toxicity. Co-administration of hydraphiles at concentration ≤ ½ MIC and antimicrobials to E. coli or P. aeruginosa showed potency enhancements of up to 30-fold. A possible mechanism is the enhancement of antibiotic influx owing to membrane disruption and/or altering the ion balance within the bacterial cells.
The emergence and spread of antimicrobial resistance highlights the urgent need for new antibiotics. Organoarsenicals have been used as antimicrobials since Paul Ehrlich’s salvarsan. Recently a soil bacterium was shown to produce the organoarsenical arsinothricin. We demonstrate that arsinothricin, a non-proteinogenic analog of glutamate that inhibits glutamine synthetase, is an effective broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria, suggesting that bacteria have evolved the ability to utilize the pervasive environmental toxic metalloid arsenic to produce a potent antimicrobial. With every new antibiotic, resistance inevitably arises. ThearsN1gene, widely distributed in bacterial arsenic resistance (ars) operons, selectively confers resistance to arsinothricin by acetylation of the α-amino group. Crystal structures of ArsN1N-acetyltransferase, with or without arsinothricin, shed light on the mechanism of its substrate selectivity. These findings have the potential for development of a new class of organoarsenical antimicrobials and ArsN1 inhibitors.
Rodríguez, Israel; Fernández-Vega, Lauren; Maser-Figueroa, Andrea N.; Sang, Branlee; González-Pagán, Patricia; Tinoco, Arthur D.(
, Antibiotics)
Due to the rapid mutation of pathogenic microorganisms, drug-resistant superbugs have evolved. Antimicrobial-resistant germs may share their resistance genes with other germs, making them untreatable. The search for more combative antibiotic compounds has led researchers to explore metal-based strategies centered on perturbing the bioavailability of essential metals in microbes and examining the therapeutic potential of metal complexes. Given the limited knowledge on the application of titanium(IV), in this work, eight Ti(IV) complexes and some of their corresponding ligands were screened by the Community for Open Antimicrobial Drug Discovery for antimicrobial activity. The compounds were selected for evaluation because of their low cytotoxic/antiproliferative behavior against a human non-cancer cell line. At pH 7.4, these compounds vary in terms of their solution stability and ligand exchange lability; therefore, an assessment of their solution behavior provides some insight regarding the importance of the identity of the metal compound to the antimicrobial therapeutic potential. Only one compound, Ti(deferasirox)2, exhibited promising inhibitory activity against the Gram-positive bacteria methicillin-resistant Staphylococcus aureus and minimal toxicity against human cells. The ability of this compound to undergo transmetalation with labile Fe(III) sources and, as a consequence, inhibit Fe bioavailability and ribonucleotide reductase is evaluated as a possible mechanism for its antibiotic effect.
Patel, Mohit B., Garrad, Evan, Meisel, Joseph W., Negin, Saeedeh, Gokel, Michael R., and Gokel, George W. Synthetic ionophores as non-resistant antibiotic adjuvants. Retrieved from https://par.nsf.gov/biblio/10249494. RSC Advances 9.4 Web. doi:10.1039/c8ra07641c.
Patel, Mohit B., Garrad, Evan, Meisel, Joseph W., Negin, Saeedeh, Gokel, Michael R., & Gokel, George W. Synthetic ionophores as non-resistant antibiotic adjuvants. RSC Advances, 9 (4). Retrieved from https://par.nsf.gov/biblio/10249494. https://doi.org/10.1039/c8ra07641c
Patel, Mohit B., Garrad, Evan, Meisel, Joseph W., Negin, Saeedeh, Gokel, Michael R., and Gokel, George W.
"Synthetic ionophores as non-resistant antibiotic adjuvants". RSC Advances 9 (4). Country unknown/Code not available. https://doi.org/10.1039/c8ra07641c.https://par.nsf.gov/biblio/10249494.
@article{osti_10249494,
place = {Country unknown/Code not available},
title = {Synthetic ionophores as non-resistant antibiotic adjuvants},
url = {https://par.nsf.gov/biblio/10249494},
DOI = {10.1039/c8ra07641c},
abstractNote = {Antimicrobial resistance is a world-wide health care crisis. New antimicrobials must both exhibit potency and thwart the ability of bacteria to develop resistance to them. We report the use of synthetic ionophores as a new approach to developing non-resistant antimicrobials and adjuvants. Most studies involving amphiphilic antimicrobials have focused on either developing synthetic amphiphiles that show ion transport, or developing non-cytotoxic analogs of such peptidic amphiphiles as colistin. We have rationally designed, prepared, and evaluated crown ether-based synthetic ionophores (‘hydraphiles’) that show selective ion transport through bilayer membranes and are toxic to bacteria. We report here that hydraphiles exhibit a broad range of antimicrobial properties and that they function as adjuvants in concert with FDA-approved antibiotics against multi-drug resistant (MDR) bacteria. Studies described herein demonstrate that benzyl C 14 hydraphile (BC 14 H) shows high efficacy as an antimicrobial. BC 14 H, at sub-MIC concentrations, forms aggregates of ∼200 nm that interact with the surface of bacteria. Surface-active BC 14 H then localizes in the bacterial membranes, which increases their permeability. As a result, antibiotic influx into the bacterial cytosol increases in the presence of BC n Hs. Efflux pump inhibition and accumulation of substrate was also observed, likely due to disruption of the cation gradient. As a result, BC 14 H recovers the activity of norfloxacin by 128-fold against resistant Staphylococcus aureus . BC 14 H shows extremely low resistance development and is less cytotoxic than colistin. Overall, synthetic ionophores represent a new scaffold for developing efficient and non-resistant antimicrobial-adjuvants.},
journal = {RSC Advances},
volume = {9},
number = {4},
author = {Patel, Mohit B. and Garrad, Evan and Meisel, Joseph W. and Negin, Saeedeh and Gokel, Michael R. and Gokel, George W.},
editor = {null}
}
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