Design and evaluation of poly-nitrogenous adjuvants capable of potentiating antibiotics in Gram-negative bacteria

Pugh, Bryce A.; Rao, Aliyah B.; Angeles-Solano, Michelle; Grosser, Melinda R.; Brock, John W.; Murphy, Kyle E.; Wolfe, Amanda L.

doi:10.1039/d2md00041e

Cited by 4 publications

(9 citation statements)

References 33 publications

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Section: Resultsmentioning

confidence: 99%

“…Poly‐nitrogenous compounds, [5] cationic diamidine compounds, [16] and diimidazole compounds [14,15] that are not antibiotics on their own have been found to act as adjuvants that can sensitize Gram‐negative bacteria to a variety of antibiotics, which increases antibiotic activity. Specifically, we recently developed a series of pentamidine derived poly‐nitrogenous compounds that can readily accumulate in and weakly potentiate erythromycin against biofilm‐forming PA stain PA 9027 [5] . Wang and co‐workers found that polyaromatic diamidine compounds can interact with the negatively charged outer membrane of Gram‐negative bacteria such as EC, AB, and KP, which increases antibiotic activity of novobiocin, rifampicin, and clarithromycin against these strains [16] .…”

Section: Resultsmentioning

confidence: 99%

“…Common antibiotic resistance mechanisms in both Gram‐positive and Gram‐negative bacteria include upregulation of efflux pumps, antibiotic target modification, upregulation of antibiotic degrading enzymes such as β‐lactamases, and biofilm formation. Gram‐negative bacteria, like KP, PA, AB and Enterobacter spp, have an added layer of defense against antibiotics because of their additional asymmetric outer membrane (OM) comprised of phospholipids on the inner leaflet and negatively charged lipopolysaccharides on the outer leaflet, which reduces antibiotic entry into the cell [2–9] . PA specifically, which has been deemed a serious threat by the CDC, is the leading cause of death in cystic fibrosis (CF) patients.…”

Section: Introductionmentioning

confidence: 99%

“…Gram-negative bacteria, like KP, PA, AB and Enterobacter spp, have an added layer of defense against antibiotics because of their additional asymmetric outer membrane (OM) comprised of phospholipids on the inner leaflet and negatively charged lipopolysaccharides on the outer leaflet, which reduces antibiotic entry into the cell. [2][3][4][5][6][7][8][9] PA specifically, which has been deemed a serious threat by the CDC, is the leading cause of death in cystic fibrosis (CF) patients. Additionally, a recent international study found that 23 % of patient infections in intensive-care units are caused by PA. [4] Administration of β-lactam and/or aminoglycoside antibiotics, such as gentamicin, is the standard treatment for PA derived infections.…”

Section: Introductionmentioning

confidence: 99%

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Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa

Kellogg,

Pugh,

Starr

et al. 2023

ChemMedChem

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Due to the global rise in the number of antibiotic resistant bacterial infections over the past 20 years, there is a dire need for the development of small molecule antibiotics capable of overcoming resistance mechanisms in pathogenic bacteria. Antibiotic development against Gram‐negative pathogens, such as Pseudomonas aeruginosa, is especially challenging due their additional outer membrane which reduces antibiotic entry. Recently, it has been shown that a broad range of nitrogen functionality, including guanidines, amidines, primary amines, imidazolines and imidazoles, promote antibiotic and adjuvant activity in Gram‐negative bacteria, but few of these have been targeted towards Pseudomonas aeruginosa specifically despite this pathogen being deemed a critical threat by the United States Centers for Disease Control and Prevention. Herein, we examined a small series of known and unknown nitrogenous dimers, with guanidine, amidine, dimethyl amine, and pyridine functionality, for antibacterial activity against multidrug resistant Pseudomonas aeruginosa. We found that two, with bisbenzguanidine and bisbenzamidine functionality, are potent against clinical isolates of multidrug resistant and biofilm forming Pseudomonas aeruginosa.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa

Kellogg,

Pugh,

Starr

et al. 2023

ChemMedChem

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“…In addition, similarly to pentamidine, some bisbenzamidines were active against P. carinii; 21 showed submicromolar activity (IC 50 = 0.6 μM) against P. carinii pneumonia in mice .…”

Section: Discussionmentioning

confidence: 99%

CanB, a Druggable Cellular Target in Mycobacterium tuberculosis

et al. 2023

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Treatment against tuberculosis can lead to the selection of drug-resistant Mycobacterium tuberculosis strains. To tackle this serious threat, new targets from M. tuberculosis are needed to develop novel effective drugs. In this work, we aimed to provide a possible workflow to validate new targets and inhibitors by combining genetic, in silico, and enzymological approaches. CanB is one of the three M. tuberculosis β-carbonic anhydrases that catalyze the reversible reaction of CO2 hydration to form HCO3 – and H+. To this end, we precisely demonstrated that CanB is essential for the survival of the pathogen in vitro by constructing conditional mutants. In addition, to search for CanB inhibitors, conditional canB mutants were also constructed using the Pip-ON system. By molecular docking and minimum inhibitory concentration assays, we selected three molecules that inhibit the growth in vitro of M. tuberculosis wild-type strain and canB conditional mutants, thus implementing a target-to-drug approach. The lead compound also showed a bactericidal activity by the time-killing assay. We further studied the interactions of these molecules with CanB using enzymatic assays and differential scanning fluorimetry thermal shift analysis. In conclusion, the compounds identified by the in silico screening proved to have a high affinity as CanB ligands endowed with antitubercular activity.

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Subminimum Inhibitory Concentrations Tetracycline Antibiotics Induce Biofilm Formation in Minocycline-Resistant Klebsiella pneumonia by Affecting Bacterial Physical and Chemical Properties and Associated Genes Expression

Guo,

Yang,

Zhou

et al. 2024

ACS Infect. Dis.

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Biofilm formation of Klebsiella pneumoniae can protect bacteria from antibiotics and is difficult to eradicate. Thus, the influence of subinhibitory concentrations of antibiotics on bacteria is becoming increasingly important. Our study showed that subminimum inhibitory concentrations (sub-MICs) of tetracycline antibiotics can increase biofilm formation in minocyclineresistant Klebsiella pneumoniae clinical strains. However, in the bacterial adhesion and invasion experiments, the adhesion and invasion ability decreased and the survival rate of Galleria mellonella increased. Under sub-MICs of tetracycline antibiotics treatment, abnormal stretching of bacteria was observed by scanning electron microscopy. Treatment with sub-MICs of tetracyclines leads to increased surface hydrophobicity and eDNA content and decreased outer membrane permeability. The expression levels of the f imA, luxS, qseB, and qseC genes decreased, the expression level of mrkA increased, and the expression level of acrA was inconsistent under different tetracycline antibiotics treatments. Together, our results suggested that the increase in Klebsiella pneumoniae biofilm formation caused by sub-MICs of tetracycline antibiotics may occur by affecting bacterial physical and chemical properties and associated genes expression.

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Design and evaluation of poly-nitrogenous adjuvants capable of potentiating antibiotics in Gram-negative bacteria

Abstract: Antibiotic resistance has been a growing public health crisis since the 1980s. Therefore, it is essential not only to continue to develop novel antibiotics but also to develop new methods...

Cited by 4 publications

References 33 publications

Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa

Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa

CanB, a Druggable Cellular Target in Mycobacterium tuberculosis

Subminimum Inhibitory Concentrations Tetracycline Antibiotics Induce Biofilm Formation in Minocycline-Resistant Klebsiella pneumonia by Affecting Bacterial Physical and Chemical Properties and Associated Genes Expression

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