Betulinic Acid Prevents the Acquisition of Ciprofloxacin-Mediated Mutagenesis in Staphylococcus aureus

Carvalho, Alexsander Rodrigues; Martins, Arthur Lima de Berrêdo; Cutrim, Brenda da Silva; Santos, Deivid Martins; Maia, Hermerson Sousa; Silva, Mari Silma Maia da; Zagmignan, Adrielle; Silva, Maria Raimunda Chagas; Monteiro, Cristina de Andrade; Guilhon, Giselle Maria Skelding Pinheiro; Filho, Antônio José Cantanhede; Silva, Luís Cláudio Nascimento da

doi:10.3390/molecules24091757

Cited by 9 publications

(4 citation statements)

References 61 publications

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“…In the reports, the tolerance acquisition towards CFX in S. aureus has shown that the MIC increases four-fold after four passages and eight-fold after eight passages [32]. Unlike these results, the CFX derivatives in our study showed no change in the MIC values until eight passages in the same experimental conditions.…”

Section: Gene Expression Analysiscontrasting

confidence: 75%

Membrane-Targeting Triphenylphosphonium Functionalized Ciprofloxacin for Methicillin-Resistant Staphylococcus aureus (MRSA)

et al. 2020

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Multidrug-resistant (MDR) bacteria have become a severe problem for public health. Developing new antibiotics for MDR bacteria is difficult, from inception to the clinically approved stage. Here, we have used a new approach, modification of an antibiotic, ciprofloxacin (CFX), with triphenylphosphonium (TPP, PPh3) moiety via ester- (CFX-ester-PPh3) and amide-coupling (CFX-amide-PPh3) to target bacterial membranes. In this study, we have evaluated the antibacterial activities of CFX and its derivatives against 16 species of bacteria, including MDR bacteria, using minimum inhibitory concentration (MIC) assay, morphological monitoring, and expression of resistance-related genes. TPP-conjugated CFX, CFX-ester-PPh3, and CFX-amide-PPh3 showed significantly improved antibacterial activity against Gram-positive bacteria, Staphylococcus aureus, including MDR S. aureus (methicillin-resistant S. aureus (MRSA)) strains. The MRSA ST5 5016 strain showed high antibacterial activity, with MIC values of 11.12 µg/mL for CFX-ester-PPh3 and 2.78 µg/mL for CFX-amide-PPh3. The CFX derivatives inhibited biofilm formation in MRSA by more than 74.9% of CFX-amide-PPh3. In the sub-MIC, CFX derivatives induced significant morphological changes in MRSA, including irregular deformation and membrane disruption, accompanied by a decrease in the level of resistance-related gene expression. With these promising results, this method is very likely to combat MDR bacteria through a simple TPP moiety modification of known antibiotics, which can be readily prepared at clinical sites.

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Section: Gene Expression Analysiscontrasting

confidence: 75%

Membrane-Targeting Triphenylphosphonium Functionalized Ciprofloxacin for Methicillin-Resistant Staphylococcus aureus (MRSA)

et al. 2020

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“…On this topic, the literature provides contradictory evidence. For instance, according to some publications, betulinic acid is inactive against Staphylococcus aureus , Bacillus subtilis , Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, and Candida albicans (minimum inhibitory concentration (MIC) values above 256 mg/L), validating our conclusions [ 92 , 93 ]. This inactivity of betulinic acid is due to its limited solubility in water and, to a limited extent, in typical organic solvents [ 94 , 95 , 96 ].…”

Section: Discussionsupporting

confidence: 82%

Comparison of In Vitro Antimelanoma and Antimicrobial Activity of 2,3-Indolo-betulinic Acid and Its Glycine Conjugates

Lombrea

Scurtu

Magyari-Pavel

et al. 2023

Plants

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Malignant melanoma is one of the most pressing problems in the developing world. New therapeutic agents that might be effective in treating malignancies that have developed resistance to conventional medications are urgently required. Semisynthesis is an essential method for improving the biological activity and the therapeutic efficacy of natural product precursors. Semisynthetic derivatives of natural compounds are valuable sources of new drug candidates with a variety of pharmacological actions, including anticancer ones. Two novel semisynthetic derivatives of betulinic acid—N-(2,3-indolo-betulinoyl)diglycylglycine (BA1) and N-(2,3-indolo-betulinoyl)glycylglycine (BA2)—were designed and their antiproliferative, cytotoxic, and anti-migratory activity against A375 human melanoma cells was determined in comparison with known N-(2,3-indolo-betulinoyl)glycine (BA3), 2,3-indolo-betulinic acid (BA4) and naturally occurring betulinic acid (BI). A dose-dependent antiproliferative effect with IC50 values that ranged from 5.7 to 19.6 µM was observed in the series of all five compounds including betulinic acid. The novel compounds BA1 (IC50 = 5.7 µM) and BA2 (IC50 = 10.0 µM) were three times and two times more active than the parent cyclic structure B4 and natural BI. Additionally, compounds BA2, BA3, and BA4 possess antibacterial activity against Streptococcus pyogenes ATCC 19615 and Staphylococcus aureus ATCC 25923 with MIC values in the range of 13–16 µg/mL and 26–32 µg/mL, respectively. On the other hand, antifungal activity toward Candida albicans ATCC 10231 and Candida parapsilosis ATCC 22019 was found for compound BA3 with MIC 29 µg/mL. This is the first report of antibacterial and antifungal activity of 2,3-indolo-betulinic acid derivatives and also the first extended report on their anti-melanoma activity, which among others includes data on anti-migratory activity and shows the significance of amino acid side chain on the observed activity. The obtained data justify further research on the anti-melanoma and antimicrobial activity of 2,3-indolo-betulinic acid derivatives.

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“…Given this result, it can be expected that the CFX derivatives have bacterial DNA-gyrase inhibition ability (1-fold) like CFX ( Figure S8). In the reports, the tolerance acquisition towards CFX in the S. aureus has been shown that the MIC increment of 4-fold after 4-passages and 8-fold after 8-passages [33]. Unlike these results, the CFX derivatives in our study showed no change of the MIC values until 8-passages in the same experimental conditions.…”

Section: Gene Expression Analysiscontrasting

confidence: 73%

Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

Kang¹,

Sunwoo²,

Jung³

et al. 2020

Preprint

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Multidrug resistant (MDR) bacteria have become a severe problem for public health. Developing new antibiotics for MDR bacteria is difficult, from inception to the clinically approved stage. Here, we have used a new approach; we have modified the antibiotic, ciprofloxacin (CFX), with triphenylphosphonium (TPP, PPh3) moiety via ester- (CFX-ester-PPh3) and amide-coupling (CFX-ester-PPh3), to target bacterial membranes. In this study, we have evaluated the antibacterial activities of CFX and its derivatives against 16 species of bacteria, including MDR bacteria, using minimum inhibitory concentration (MIC) assay, morphological monitoring, and expression of resistance-related genes. TPP-conjugated CFX, CFX-ester-PPh3 and CFX-amide-PPh3 showed significantly improved antibacterial activity against Gram-positive bacteria, Staphylococcus aureus, including MDR S. aureus (MRSA) strains. The MRSA ST5 5016 strain showed high antibacterial activity, with an MIC values of 11.12 µg/mL for CFX-ester-PPh3 and 2.78 µg/mL for CFX-amide-PPh3. The CFX derivatives inhibited biofilm formation in MRSA by more than 74.9% of CFX-amide-PPh3. In the sub-MIC, CFX derivates induced significant morphological changes in MRSA, including irregular deformation and membrane disruption, accompanied by a decrease in the level of resistance-related gene expression. With these promising results, this method is very likely to combat MDR bacteria, through a simple TPP moiety modification of known antibiotics, which can be readily prepared at clinical sites.

show abstract

Betulinic Acid Prevents the Acquisition of Ciprofloxacin-Mediated Mutagenesis in Staphylococcus aureus

Cited by 9 publications

References 61 publications

Membrane-Targeting Triphenylphosphonium Functionalized Ciprofloxacin for Methicillin-Resistant Staphylococcus aureus (MRSA)

Membrane-Targeting Triphenylphosphonium Functionalized Ciprofloxacin for Methicillin-Resistant Staphylococcus aureus (MRSA)

Comparison of In Vitro Antimelanoma and Antimicrobial Activity of 2,3-Indolo-betulinic Acid and Its Glycine Conjugates

Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

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