Membrane-Active Nonivamide Derivatives as Effective Broad-Spectrum Antimicrobials: Rational Design, Synthesis, and Biological Evaluation

Cai, Qiongna; Yu, Qian; Liang, Wanxin; Li, Haizhou; Liu, Jiayong; Li, Hongxia; Chen, Yongzhi; Fang, Shanfang; Zhong, Rongcui; Liu, Shouping; Lin, Shuimu

doi:10.1021/acs.jmedchem.2c01604

Cited by 10 publications

(4 citation statements)

References 46 publications

(124 reference statements)

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“…When the Gram-negative bacteria’s outer membrane is disturbed, N -phenyl-1-naphthylamine (NPN) can penetrate the hydrophobic environment inside the cell and fluoresce . The degree of outer membrane permeabilization of peptides increased with concentration (Figure b).…”

Section: Resultsmentioning

confidence: 99%

“…When the Gram-negative bacteria's outer membrane is disturbed, N-phenyl-1-naphthylamine (NPN) can penetrate the hydrophobic environment inside the cell and fluoresce. 28 The degree of outer membrane permeabilization of peptides increased with concentration (Figure 2b). However, peptide KLR only permeabilized to the E. coli outer membrane at a rate of up to 69.3% ± 5.13% at 8 μM concentration, which was lower than ME.…”

Section: Design and Synthesis Of Cationic End-tagging Shortmentioning

confidence: 94%

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Engineered Peptides Harboring Cation Motifs Against Multidrug-Resistant Bacteria

Shang,

Chen,

Sun

et al. 2024

ACS Appl. Mater. Interfaces

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Multidrug-resistant (MDR) pathogens pose a serious threat to the health and life of humans, necessitating the development of new antimicrobial agents. Herein, we develop and characterize a panel of nine amino acid peptides with a cation end motif. Bioactivity analysis revealed that the short peptide containing "RWWWR" as a central motif harboring mirror structure "KXR" unit displayed not only high activity against MDR planktonic bacteria but also a clearance rate of 92.33% ± 0.58% against mature biofilm. Mechanically, the target peptide (KLR) killed pathogens by excessively accumulating reactive oxygen species and physically disrupting membranes, thereby enhancing its robustness for controlling drug resistance. In the animal model of sepsis infection by MDR bacteria, the peptide KLR exhibited strong therapeutic effects. Collectively, this study provided the dominant structure of short antimicrobial peptides (AMPs) to replenish our arsenals for combating bacterial infections and illustrated what could be harnessed as a new agent for fighting MDR bacteria.

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Section: Resultsmentioning

confidence: 99%

Section: Design and Synthesis Of Cationic End-tagging Shortmentioning

confidence: 94%

Engineered Peptides Harboring Cation Motifs Against Multidrug-Resistant Bacteria

Shang,

Chen,

Sun

et al. 2024

ACS Appl. Mater. Interfaces

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“…The development of bacterial resistance leads to a reduction in the activity of clinical drugs, and the solution is often the dosage of intensification, which will not only cause adverse drug reactions in humans but also further aggravate the development of drug resistance [ 40 , 41 , 42 ]. Therefore, it is urgent to develop new drug candidates with low drug resistance tendencies.…”

Section: Resultsmentioning

confidence: 99%

“…Molecules 2023, 28, x FOR PEER REVIEW 8 of 26 resistance [40][41][42]. Therefore, it is urgent to develop new drug candidates with low drug resistance tendencies.…”

Section: Resistance Studymentioning

confidence: 99%

Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a

et al. 2023

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Bacterial infections caused by methicillin-resistant Staphylococcus aureus have seriously threatened public health. There is an urgent need to propose an existing regimen to overcome multidrug resistance of MRSA. A unique class of novel anti-MRSA thiazolylketenyl quinazolinones (TQs) and their analogs were developed. Some synthesized compounds showed good bacteriostatic potency. Especially TQ 4 was found to exhibit excellent inhibition against MRSA with a low MIC of 0.5 μg/mL, which was 8-fold more effective than norfloxacin. The combination of TQ 4 with cefdinir showed stronger antibacterial potency. Further investigation revealed that TQ 4, with low hemolytic toxicity and low drug resistance, was not only able to inhibit biofilm formation but also could reduce MRSA metabolic activity and showed good drug-likeness. Mechanistic explorations revealed that TQ 4 could cause leakage of proteins by disrupting membrane integrity and block DNA replication by intercalated DNA. Furthermore, the synergistic antibacterial effect with cefdinir might be attributed to TQ 4 with the ability to induce PBP2a allosteric regulation of MRSA and further trigger the opening of the active site to promote the binding of cefdinir to the active site, thus inhibiting the expression of PBP2a, thereby overcoming MRSA resistance and significantly enhancing the anti-MRSA activity of cefdinir. A new strategy provided by these findings was that TQ 4, possessing both excellent anti-MRSA activity and allosteric effect of PBP2a, merited further development as a novel class of antibacterial agents to overcome increasingly severe MRSA infections.

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Pyridine‐2,6‐Dicarboxamide Proligands and their Cu(II)/Zn(II) Complexes Targeting Staphylococcus Aureus for the Attenuation of In Vivo Dental Biofilm

Chaudhary,

Agrahari,

Biswas

et al. 2024

Adv Healthcare Materials

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In the pursuit to combat stubborn bacterial infections, particularly those stemming from gram‐positive bacteria, our study is an attempt to craft a precision‐driven platform characterized by unparalleled selectivity, specificity, and synergistic antimicrobial mechanisms. Leveraging remarkable potential of metalloantibiotics in antimicrobial applications, herein, we rationally design, synthesize, and characterize a new library of Pyridine‐2,6‐dicarboxamide ligands and their corresponding transition metal Cu(II)/Zn(II) complexes. The lead compound L11 demonstrate robust antibacterial properties against Staphylococcus aureus (MIC = 2‐16 µg/mL), methicillin and vancomycin‐resistant S. aureus (MIC = 2‐4 µg/mL) and exhibit superior antibacterial activity when compared to FDA‐approved vancomycin, the drug of last resort. Additionally, the compound exhibited notable antimicrobial efficacy against resistant enterococcus strains (MIC = 2‐8 µg/mL). To unravel mechanistic profile, advanced imaging techniques including SEM and AFM were harnessed, collectively suggesting a mechanistic pathway involving cell wall disruption. Live/dead fluorescence studies further confirm efficacy of L11 and its complexes against S. aureus membranes. Our translational exploration extends to a rat model, indicating promising In‐vivo therapeutic potential. Thus, our comprehensive research initiative has capabilities to transcends the confines of our laboratory, heralding a pivotal step toward combatting antibiotic‐resistant pathogens and advancing the frontiers of metalloantibiotics based therapy with a profound clinical implication.This article is protected by copyright. All rights reserved

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Membrane-Active Nonivamide Derivatives as Effective Broad-Spectrum Antimicrobials: Rational Design, Synthesis, and Biological Evaluation

Cited by 10 publications

References 46 publications

Engineered Peptides Harboring Cation Motifs Against Multidrug-Resistant Bacteria

Engineered Peptides Harboring Cation Motifs Against Multidrug-Resistant Bacteria

Novel Thiazolylketenyl Quinazolinones as Potential Anti-MRSA Agents and Allosteric Modulator for PBP2a

Pyridine‐2,6‐Dicarboxamide Proligands and their Cu(II)/Zn(II) Complexes Targeting Staphylococcus Aureus for the Attenuation of In Vivo Dental Biofilm

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