Effects of sub-minimum inhibitory concentrations of ciprofloxacin on biofilm formation and virulence factors of Escherichia coli

Dong, Guofeng; Li, Jiahui; Chen, Lijiang; Bi, Wenzi; Zhang, Xiaoxiao; Liu, Haiyang; Zhi, Xiao‐Yang; Zhou, Tieli; Cao, Jianming

doi:10.1016/j.bjid.2019.01.004

Cited by 24 publications

(25 citation statements)

References 20 publications

(30 reference statements)

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“…We observed variability in this phenotype across OM perturbants—EDTA, SPR741, and the genetic deletion of waaC reduced biofilm formation, while pentamidine and colistin increased biofilm formation. We reason that this increase may be attributed to the known ability for subinhibitory concentrations of antibiotics to stimulate biofilm formation ( 44 , 45 ). That some OM perturbants impair biofilm formation is encouraging, particularly for guidelines that may be implemented to prioritize OM perturbants for further development.…”

Section: Discussionmentioning

confidence: 99%

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

MacNair

Brown

2020

mBio

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Disruption of the outer membrane (OM) barrier allows for the entry of otherwise inactive antimicrobials into Gram-negative pathogens. Numerous efforts to implement this approach have identified a large number of OM perturbants that sensitize Gram-negative bacteria to many clinically available Gram-positive active antibiotics. However, there is a dearth of investigation into the strengths and limitations of this therapeutic strategy, with an overwhelming focus on characterization of individual potentiator molecules. Herein, we look to explore the utility of exploiting OM perturbation to sensitize Gram-negative pathogens to otherwise inactive antimicrobials. We identify the ability of OM disruption to change the rules of Gram-negative entry, overcome preexisting and spontaneous resistance, and impact biofilm formation. Disruption of the OM expands the threshold of hydrophobicity compatible with Gram-negative activity to include hydrophobic molecules. We demonstrate that while resistance to Gram-positive active antibiotics is surprisingly common in Gram-negative pathogens, OM perturbation overcomes many antibiotic inactivation determinants. Further, we find that OM perturbation reduces the rate of spontaneous resistance to rifampicin and impairs biofilm formation. Together, these data suggest that OM disruption overcomes many of the traditional hurdles encountered during antibiotic treatment and is a high priority approach for further development. IMPORTANCE The spread of antibiotic resistance is an urgent threat to global health that necessitates new therapeutics. Treatments for Gram-negative pathogens are particularly challenging to identify due to the robust outer membrane permeability barrier in these organisms. Recent discovery efforts have attempted to overcome this hurdle by disrupting the outer membrane using chemical perturbants and have yielded several new peptides and small molecules that allow the entry of otherwise inactive antimicrobials. However, a comprehensive investigation into the strengths and limitations of outer membrane perturbants as antibiotic partners is currently lacking. Herein, we interrogate the interaction between outer membrane perturbation and several common impediments to effective antibiotic use. Interestingly, we discover that outer membrane disruption is able to overcome intrinsic, spontaneous, and acquired antibiotic resistance in Gram-negative bacteria, meriting increased attention toward this approach.

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Section: Discussionmentioning

confidence: 99%

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

MacNair

Brown

2020

mBio

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“…A total of 96 microporous culture plates were studied, and the crystal violet staining method was used to quantitatively analyze the bacterial biofilm formation, similar to previous studies [21][22][23]. Moreover, scanning electron microscopy can be used to directly observe the formation of bacterial biofilm, as has previously been carried out for Staphylococcus aureus and Escherichia coli biofilm [24][25][26]. To investigate the relationship between culture conditions and biofilm formation ability, the temperature, pH, and culture medium were chosen as variables for experimental conditions.…”

Section: Discussionmentioning

confidence: 92%

An iTRAQ-Based Comparative Proteomics Analysis of the Biofilm and Planktonic States of Aeromonas veronii TH0426

Li¹,

Yang²,

Tian³

et al. 2020

IJMS

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Aeromonas veronii is a virulent fish pathogen that causes extensive economic losses in the aquaculture industry worldwide. In this study, a virulent strain of A. veronii TH0426 was used to establish an in vitro biofilm model. The results show that the biofilm-forming abilities of A. veronii TH0426 were similar in different media, peaking under conditions of 20 °C and pH 6. Further, isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics methods were used to compare the differential expression of A. veronii between the biofilm and planktonic cells. The results show alterations in 277 proteins, with 130 being upregulated and 147 downregulated. Pathway analysis and GO (Gene Ontology) annotations indicated that these proteins are mainly involved in metabolic pathways and the biosynthesis of secondary metabolites and antibiotics. These proteins are the main factors affecting the adaptability of A. veronii to its external environment. MRM (multiple reaction 27 monitoring) and qPCR (qPCR) were used to verify the differential proteins of the selected A. veronii. This is the first report on the biofilm and planktonic cells of A. veronii, thus contributing to studying the infection and pathogenesis of A. veronii.

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“…Unlike these results, the CFX derivatives in our study showed no change of the MIC values until 8-passages in the same experimental conditions. The CFX resistance of S. aureus has genetically evolved via the acquisition of mutations in the gyrA or the norA gene following as; (i) accelerating the multidrug efflux pumps (MDEPs) such as norA, sepA, and medA, (ii) generating mutations at the quinolone resistancedetermining regions (QRDRs) to reduce the affinity of the CFX [34]. We concluded that the CFX-PPh3 derivatives have excellent antibacterial activity by inhibition of DNA gyrase and efflux pump ability.…”

Section: Gene Expression Analysismentioning

confidence: 99%

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.

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Effects of sub-minimum inhibitory concentrations of ciprofloxacin on biofilm formation and virulence factors of Escherichia coli

Cited by 24 publications

References 20 publications

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

Outer Membrane Disruption Overcomes Intrinsic, Acquired, and Spontaneous Antibiotic Resistance

An iTRAQ-Based Comparative Proteomics Analysis of the Biofilm and Planktonic States of Aeromonas veronii TH0426

Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

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