Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206

Brown, Pamela; Abbott, Elizabeth; Abdulle, Omar; Boakes, Steven; Coleman, Scott; Divall, Naomi; Duperchy, Esther; Moss, Stephen; Rivers, Dean; Simonovic, Mona; Singh, Jaspal; Stanway, Steven J.; Wilson, Antoinette; Dawson, Michael J.

doi:10.1021/acsinfecdis.9b00217

Cited by 58 publications

(79 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These compounds demonstrated superior in vitro activity and inferior cytotoxicity compared to polymyxin B. A subgroup of these compounds having a β-branched aminobutyrate N-terminus with an aryl substituent also offered low cytotoxicity, and candidates were selected for additional development [ 221 ]. The future holds potential for these drug discovery and development programs to bring upgraded polymyxins or novel polymyxin-including combinations from the bench into the clinic.…”

Section: Future Implicationsmentioning

confidence: 99%

Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

2020

View full text Add to dashboard Cite

Following their initial discovery in the 1940s, polymyxin antibiotics fell into disfavor due to their potential clinical toxicity, especially nephrotoxicity. However, the dry antibiotic development pipeline, together with the rising global prevalence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria have both rejuvenated clinical interest in these polypeptide antibiotics. Parallel to the revival of their use, investigations into the mechanisms of action and resistance to polymyxins have intensified. With an initial known effect on biological membranes, research has uncovered the detailed molecular and chemical interactions that polymyxins have with Gram-negative outer membranes and lipopolysaccharide structure. In addition, genetic and epidemiological studies have revealed the basis of resistance to these agents. Nowadays, resistance to polymyxins in MDR Gram-negative pathogens is well elucidated, with chromosomal as well as plasmid-encoded, transferrable pathways. The aims of the current review are to highlight the important chemical, microbiological, and pharmacological properties of polymyxins, to discuss their mechanistic effects on bacterial membranes, and to revise the current knowledge about Gram-negative acquired resistance to these agents. Finally, recent research, directed towards new perspectives for improving these old agents utilized in the 21st century, to combat drug-resistant pathogens, is summarized.

show abstract

Section: Future Implicationsmentioning

confidence: 99%

Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

2020

View full text Add to dashboard Cite

show abstract

“…Examples include polymyxins or lipodepsipeptide daptomycin, whose 'tail' aa and lipophilic groups were altered, or depsipeptides ramoplanin and telomycin, whose acylation patterns were modified. [356][357][358][359][360]…”

Section: Semi-synthetic Ampsmentioning

confidence: 99%

The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Therefore, researchers have attempted to develop derivatives of polymyxin to improve its properties. Analogs of polymyxin, SPR741, SPR1205, SPR206, and SPR946 have been designed by shortening the peptide chains, by modifying the acyl chains, and by substituting the amino acid residues to reduce nephrotoxicity and to improve potency [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. SPR206 is a novel polymyxin B analog for the treatment of gram-negative infection that is undergoing a phase I clinical trial [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

Krishnan

Choi

Jang

et al. 2020

IJMS

View full text Add to dashboard Cite

Owing to the challenges faced by conventional therapeutics, novel peptide antibiotics against multidrug-resistant (MDR) gram-negative bacteria need to be urgently developed. We had previously designed Pro9-3 and Pro9-3D from the defensin of beetle Protaetia brevitarsis; they showed high antimicrobial activity with cytotoxicity. Here, we aimed to develop peptide antibiotics with bacterial cell selectivity and potent antibacterial activity against gram-negative bacteria. We designed 10-meric peptides with increased cationicity by adding Arg to the N-terminus of Pro9-3 (Pro10-1) and its D-enantiomeric alteration (Pro10-1D). Among all tested peptides, the newly designed Pro10-1D showed the strongest antibacterial activity against Escherichia coli, Acinetobacter baumannii, and MDR strains with resistance against protease digestion. Pro10-1D can act as a novel potent peptide antibiotic owing to its outstanding inhibitory activities against bacterial film formation with high bacterial cell selectivity. Dye leakage and scanning electron microscopy revealed that Pro10-1D targets the bacterial membrane. Pro10-1D inhibited inflammation via Toll Like Receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) signaling pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Furthermore, Pro10-1D ameliorated multiple-organ damage and attenuated systemic infection-associated inflammation in an E. coli K1-induced sepsis mouse model. Overall, our results suggest that Pro10-1D can potentially serve as a novel peptide antibiotic for the treatment of gram-negative sepsis.

show abstract

Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206

Cited by 58 publications

References 30 publications

Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models

Contact Info

Product

Resources

About