Identification of a Novel Protein Synthesis Inhibitor Active against Gram‐Positive Bacteria

Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections.

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“…Haemolysis assays were performed as previously described 55 . Briefly, assays were performed using human erythrocytes within 3 days of receipt.…”

Section: Methodsmentioning

confidence: 99%

Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

et al. 2015

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“…In the first phase of this work, attention was paid to the construction of a QSAR model, through the VolSurf+ software, for the evaluation of the microbiological activity of heteroaryl-ethylenes. Although few data have been reported for this kind of synthetic derivatives, [21,[25][26][27][28][29][30][31][32][33][34] it was possible to take advantage of the data available for stilbenic molecules mainly derived from natural source. One of the most investigated bacterial strain is S. aureus ATCC29213, and this allowed us to build up the PLS model: the aim of this kind of statistical and molecular modelling approach is to highlight promising scaffolds.…”

Section: Discussionmentioning

confidence: 99%

“…[35] The data for the microbiological activity, expressed as MIC (mg/L), of 40 heteroaryl and stilbenoids compounds (Table S1) tested on S. aureus ATCC29213 constituted our library for the prediction of the antibacterial activity. [21,[25][26][27][28][29][30][31][32][33][34] The PLS model obtained allowed us to locate the most active compounds in the upper left side of the 2D Scores plot (Figure 1). The biological/chemical space represented by the PLS t1/t2 scores plot was properly explored and the model showed high predictive accuracy (R 2 = 0.88).…”

Section: Volsurf+ Analysismentioning

confidence: 99%

“…Further exploration of these structures, from both a synthetic and a microbiological perspective, will be the focus of this work. A preliminary antimicrobial structure-activity relationship (SAR) investigation was performed, using forty stilbenic and heteroaromatic compounds whose antimicrobial activity towards S. aureus was previously reported, [21,[25][26][27][28][29][30][31][32][33][34] in order to select eight promising candidates (PB1-8, see Scheme S1).…”

Section: Introductionmentioning

confidence: 99%

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Heteroaryl-Ethylenes as New Lead Compounds in the Fight against High Priority Bacterial Strains

Bongiorno¹,

Musso²,

Bonacci³

et al. 2021

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The widespread use of antibiotics has led to a gradual increase in drug-resistant bacterial infections, which severely weakens the clinical efficacy of antibacterial therapies. In recent decades, stilbenes aroused great interest because of their high bioavailability, as well as for their manifold biological activity. Our research efforts are focused on synthetic heteroaromatic stilbene deriva-tives as they represent a potentially new type of antibiotic with a wide antibacterial spectrum. Herein, a preliminary molecular modeling study and a versatile synthetic scheme allowed us to define eight heteroaromatic stilbene derivatives with potential antimicrobial activity. In order to evaluate our compound’s activity spectrum and antibacterial ability, Minimum Inhibitory Con-centration (MIC) and Minimum Bactericidal Concentration (MBC) tests have been performed on Gram-positive and Gram-negative ATCC strains. Compounds PB4, PB5, PB7 and PB8 showed the best values in terms of MIC and were also evaluated for MBC, which however was found to be greater than MIC, confirming a bacteriostatic activity. For all compounds, we evaluated toxici-ty on colon-rectal adenocarcinoma cells tumor cells (CaCo2), once established that the whole se-lected set was more active than 5-Fluorouracil in reducing CaCo-2 cells viability. To the best of our knowledge, the biological assays have shown for these derivatives an excellent bacteriostatic activity, compared to similar molecular structures previously reported, thus paving the way for a new class of antibiotic compounds.

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“…Further exploration of these structures, from both a synthetic and a microbiological perspective, will be the focus of this work. A preliminary antimicrobial structure-activity relationship (SAR) investigation was performed, using forty stilbenic and heteroaromatic compounds whose antimicrobial activity towards S. aureus was previously reported [ 22 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ], in order to select eight promising candidates (PB1-8, see Scheme S1 ).…”

Section: Introductionmentioning

confidence: 99%

Heteroaryl-Ethylenes as New Lead Compounds in the Fight against High Priority Bacterial Strains

et al. 2021

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The widespread use of antibiotics has led to a gradual increase in drug-resistant bacterial infections, which severely weakens the clinical efficacy of antibacterial therapies. In recent decades, stilbenes aroused great interest because of their high bioavailability, as well as their manifold biological activity. Our research efforts are focused on synthetic heteroaromatic stilbene derivatives as they represent a potentially new type of antibiotic with a wide antibacterial spectrum. Herein, a preliminary molecular modeling study and a versatile synthetic scheme allowed us to define eight heteroaromatic stilbene derivatives with potential antimicrobial activity. In order to evaluate our compound’s activity spectrum and antibacterial ability, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests have been performed on Gram-positive and Gram-negative ATCC strains. Compounds PB4, PB5, PB7, and PB8 showed the best values in terms of MIC and were also evaluated for MBC, which was found to be greater than MIC, confirming a bacteriostatic activity. For all compounds, we evaluated toxicity on colon-rectal adenocarcinoma cells tumor cells (CaCo2), once it was established that the whole selected set was more active than 5-Fluorouracil in reducing CaCo-2 cells viability. To the best of our knowledge, the biological assays have shown for these derivatives an excellent bacteriostatic activity, compared to similar molecular structures previously reported, thus paving the way for a new class of antibiotic compounds.

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Identification of a Novel Protein Synthesis Inhibitor Active against Gram‐Positive Bacteria

Cited by 5 publications

References 37 publications

Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

Heteroaryl-Ethylenes as New Lead Compounds in the Fight against High Priority Bacterial Strains

Heteroaryl-Ethylenes as New Lead Compounds in the Fight against High Priority Bacterial Strains

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