More Like this

1. Rational Framework for the Design of Trp- and Arg-Rich Peptide Antibiotics Against Multidrug-Resistant Bacteria

   https://doi.org/10.3389/fmicb.2022.889791  

   Xiang, Wenyu ; Clemenza, Patrice ; Klousnitzer, Jessie ; Chen, Jespar ; Qin, Weiheng ; Tristram-Nagle, Stephanie ; Doi, Yohei ; Di, Y. Peter ; Deslouches, Berthony ( May 2022 , Frontiers in Microbiology)

   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.more »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.« less
2. Amphiphilic polymer therapeutics: an alternative platform in the fight against antibiotic resistant bacteria

   https://doi.org/10.1039/D0BM01865A  

   Takahashi, Haruko ; Caputo, Gregory A. ; Kuroda, Kenichi ( April 2021 , Biomaterials Science)

   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.
3. Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broad-spectrum antibiotic

   https://doi.org/10.1038/s42003-019-0365-y  

   Nadar, Venkadesh Sarkarai ; Chen, Jian ; Dheeman, Dharmendra S. ; Galván, Adriana Emilce ; Yoshinaga-Sakurai, Kunie ; Kandavelu, Palani ; Sankaran, Banumathi ; Kuramata, Masato ; Ishikawa, Satoru ; Rosen, Barry P. ; et al ( April 2019 , Communications Biology)

   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.
4. Resensitization of Resistant Bacteria to Antimicrobials

   Patel, Mohit B. ; Meisel, Joseph W. ; Negin, Saeedeh ; Gokel, Michael R. ; Garrad, Evan ; Gokel, George W. ( April 2017 , Annals of pharmacology and pharmaceutics)

   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.
5. Chronic exposure to complex metal oxide nanoparticles elicits rapid resistance in Shewanella oneidensis MR-1

   https://doi.org/10.1039/C9SC01942A  

   Mitchell, Stephanie L. ; Hudson-Smith, Natalie V. ; Cahill, Meghan S. ; Reynolds, Benjamin N. ; Frand, Seth D. ; Green, Curtis M. ; Wang, Chenyu ; Hang, Mimi N. ; Hernandez, Rodrigo Tapia ; Hamers, Robert J. ; et al ( January 2019 , Chemical Science)

   Engineered nanoparticles are incorporated into numerous emerging technologies because of their unique physical and chemical properties. Many of these properties facilitate novel interactions, including both intentional and accidental effects on biological systems. Silver-containing particles are widely used as antimicrobial agents and recent evidence indicates that bacteria rapidly become resistant to these nanoparticles. Much less studied is the chronic exposure of bacteria to particles that were not designed to interact with microorganisms. For example, previous work has demonstrated that the lithium intercalated battery cathode nanosheet, nickel manganese cobalt oxide (NMC), is cytotoxic and causes a significant delay in growth of Shewanella oneidensis MR-1 upon acute exposure. Here, we report that S. oneidensis MR-1 rapidly adapts to chronic NMC exposure and is subsequently able to survive in much higher concentrations of these particles, providing the first evidence of permanent bacterial resistance following exposure to nanoparticles that were not intended as antibacterial agents. We also found that when NMC-adapted bacteria were subjected to only the metal ions released from this material, their specific growth rates were higher than when exposed to the nanoparticle. As such, we provide here the first demonstration of bacterial resistance to complex metal oxide nanoparticles with an adaptation mechanismmore »that cannot be fully explained by multi-metal adaptation. Importantly, this adaptation persists even after the organism has been grown in pristine media for multiple generations, indicating that S. oneidensis MR-1 has developed permanent resistance to NMC.« less