scholarly journals Quinolone Resistance Reversion by Targeting the SOS Response

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
E. Recacha ◽  
J. Machuca ◽  
P. Díaz de Alba ◽  
M. Ramos-Güelfo ◽  
F. Docobo-Pérez ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Antimicrobial Agents ◽  
Sos Response ◽  
Resistance Mechanisms ◽  
Quinolone Resistance ◽  
Resistant Bacteria ◽  
Health Crisis ◽  
E Coli ◽  
Isogenic Strains

ABSTRACT Suppression of the SOS response has been postulated as a therapeutic strategy for potentiating antimicrobial agents. We aimed to evaluate the impact of its suppression on reversing resistance using a model of isogenic strains of Escherichia coli representing multiple levels of quinolone resistance. E. coli mutants exhibiting a spectrum of SOS activity were constructed from isogenic strains carrying quinolone resistance mechanisms with susceptible and resistant phenotypes. Changes in susceptibility were evaluated by static (MICs) and dynamic (killing curves or flow cytometry) methodologies. A peritoneal sepsis murine model was used to evaluate in vivo impact. Suppression of the SOS response was capable of resensitizing mutant strains with genes encoding three or four different resistance mechanisms (up to 15-fold reductions in MICs). Killing curve assays showed a clear disadvantage for survival (Δlog10 CFU per milliliter [CFU/ml] of 8 log units after 24 h), and the in vivo efficacy of ciprofloxacin was significantly enhanced (Δlog10 CFU/g of 1.76 log units) in resistant strains with a suppressed SOS response. This effect was evident even after short periods (60 min) of exposure. Suppression of the SOS response reverses antimicrobial resistance across a range of E. coli phenotypes from reduced susceptibility to highly resistant, playing a significant role in increasing the in vivo efficacy. IMPORTANCE The rapid rise of antibiotic resistance in bacterial pathogens is now considered a major global health crisis. New strategies are needed to block the development of resistance and to extend the life of antibiotics. The SOS response is a promising target for developing therapeutics to reduce the acquisition of antibiotic resistance and enhance the bactericidal activity of antimicrobial agents such as quinolones. Significant questions remain regarding its impact as a strategy for the reversion or resensitization of antibiotic-resistant bacteria. To address this question, we have generated E. coli mutants that exhibited a spectrum of SOS activity, ranging from a natural SOS response to a hypoinducible or constitutively suppressed response. We tested the effects of these mutations on quinolone resistance reversion under therapeutic concentrations in a set of isogenic strains carrying different combinations of chromosome- and plasmid-mediated quinolone resistance mechanisms with susceptible, low-level quinolone resistant, resistant, and highly resistant phenotypes. Our comprehensive analysis opens up a new strategy for reversing drug resistance by targeting the SOS response. IMPORTANCE The rapid rise of antibiotic resistance in bacterial pathogens is now considered a major global health crisis. New strategies are needed to block the development of resistance and to extend the life of antibiotics. The SOS response is a promising target for developing therapeutics to reduce the acquisition of antibiotic resistance and enhance the bactericidal activity of antimicrobial agents such as quinolones. Significant questions remain regarding its impact as a strategy for the reversion or resensitization of antibiotic-resistant bacteria. To address this question, we have generated E. coli mutants that exhibited a spectrum of SOS activity, ranging from a natural SOS response to a hypoinducible or constitutively suppressed response. We tested the effects of these mutations on quinolone resistance reversion under therapeutic concentrations in a set of isogenic strains carrying different combinations of chromosome- and plasmid-mediated quinolone resistance mechanisms with susceptible, low-level quinolone resistant, resistant, and highly resistant phenotypes. Our comprehensive analysis opens up a new strategy for reversing drug resistance by targeting the SOS response.

scholarly journals Cranberry-Derived Proanthocyanidins Potentiate β-Lactam Antibiotics Against Resistant Bacteria

2021 ◽  
Author(s):  
Mathias Gallique ◽  
Kuan Wei ◽  
Vimal B. Maisuria ◽  
Mira Okshevsky ◽  
Geoffrey McKay ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Antimicrobial Agents ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
E Coli ◽  
New Generation ◽  
Future Work ◽  
Emergence Of Resistance

The emergence and spread of extended-spectrum β-lactamases (ESBLs), metallo-β-lactamases (MBLs) or variant low affinity penicillin-binding proteins (PBPs) pose a major threat to our ability to treat bacterial infection using β-lactam antibiotics. Although combinations of β-lactamase inhibitors with β-lactam agents have been clinically successful, there are no MBL inhibitors in current therapeutic use. Furthermore, recent clinical use of new generation cephalosporins targeting PBP2a, an altered PBP, has led to the emergence of resistance to these antimicrobial agents. Previous work shows that natural polyphenols such as cranberry-extracted proanthocyanidins (cPAC) can potentiate non-β-lactam antibiotics against Gram-negative bacteria. This study extends beyond previous work by investigating the in vitro effect of cPAC in overcoming ESBL-, MBL- and PBP2a-mediated β-lactam resistance. The results show that cPAC exhibit variable potentiation of different β-lactams against β-lactam resistant Enterobacteriaceae clinical isolates as well as ESBL- and MBL-producing E. coli. We also discovered that cPAC have broad-spectrum inhibitory properties in vitro on the activity of different classes of β-lactamases, including CTX-M3 ESBL and IMP-1 MBL. Furthermore, we observe that cPAC selectively potentiate oxacillin and carbenicillin against methicillin-resistant but not methicillin-sensitive Staphylococci, suggesting that cPAC also interfere with PBP2a-mediated resistance. This study motivates the need for future work to identify the most bioactive compounds in cPAC and to evaluate their antibiotic potentiating efficacy in vivo. IMPORTANCE Emergence of β-lactam resistant Enterobacteriaceae and Staphylococci compromised the efficiency of β-lactams-based therapy. By acquisition of ESBLs, MBLs or PBPs, it is highly likely that bacteria become completely resistant to the most efficient β-lactam agents in the near future. In this study, we described a natural extract rich in proanthocyanidins which exerts adjuvant properties by interfering with two different resistance mechanisms. By their broad-spectrum inhibitory ability, cranberry-extracted proanthocyanidins could have the potential to enhance effectiveness of existing β-lactam agents.

scholarly journals Quinolone resistance (qnrA) gene in isolates of Escherichia coli collected from the Al-Hillah River in Babylon Province, Iraq

Pharmacia ◽  
2021 ◽  
Vol 68 (1) ◽  
pp. 1-7
Author(s):  
Hawraa Mohammed Al-Rafyai ◽  
Mourouge Saadi Alwash ◽  
Noor Salman Al-Khafaji
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Antibiotic Resistance Genes ◽  
Quinolone Resistance ◽  
Resistant Bacteria ◽  
Global Public Health ◽  
Phenotypic Resistance ◽  
E Coli ◽  
Potential Reservoir ◽  
Public Health Hazards

Aquatic environment contamination remains a foremost global public health hazards, and symbolizes a significant reservoir of releasing antibiotic resistant bacteria. The survival of Escherichia coli in aquatic environments serves as a potential reservoir of antibiotic resistance, encompassing but not restricted to a plasmid-mediated quinolone resistance (PMQR) mechanism. The current study aimed to detect the presence of the PMQR-qnrA gene in quinolone-resistant E. coli isolates. Sixty-one waterborne E. coli with known phylogroups/subgroups isolated from the Al-Hillah River in Babylon Province, Iraq, were screened for the phenotypic resistance to third-generation quinolones (levofloxacin and ofloxacin) and were further analysed for the presence of the qnrA gene using polymerase chain reaction (PCR). Fifty-seven (93.4%) of 61 E. coli isolates were levofloxacin-resistant, and 55 (90.2%) were ofloxacin-resistant. Among the 57 quinolone-resistant E. coli, 40 (65.57%) isolates were found to carry the PMQR-qnrA gene. Among the 40 qnrA-positive E. coli, 22 (36.1%) isolates were in phylogroup B2, followed by 8 (13.1%) isolates in phylogroup D, 6 (9.8%) isolates in phylogroup B1, and 4 (6.6%) isolates in phylogroup A. The presence of the PMQR-qnrA gene in E. coli belonging to phylogroup B2 and D reflects the need for routine monitoring of antibiotic resistance genes (ARGs) in the Al-Hillah River.

scholarly journals Prevalence and Mechanism of Fluoroquinolone Resistance in Escherichia coli Isolated from Swine Feces in Korea

2017 ◽  
Vol 80 (7) ◽  
pp. 1145-1151 ◽  
Author(s):  
Yoon Sung Hu ◽  
Sook Shin ◽  
Yong Ho Park ◽  
Kun Taek Park
Keyword(s):  
Escherichia Coli ◽  
Resistance Genes ◽  
Resistance Mechanisms ◽  
Quinolone Resistance ◽  
Feed Additive ◽  
Diffusion Method ◽  
Resistant Bacteria ◽  
Double Mutation ◽  
Fecal Samples ◽  
E Coli

ABSTRACT In this study, we investigated the prevalence and fluoroquinolone (FQ) resistance mechanisms in Escherichia coli isolated from swine fecal samples. E. coli isolates were collected from 171 (72.2%) of 237 swine fecal samples. Of these, 59 isolates (34.5%) were confirmed as FQ-resistant E. coli by the disk diffusion method. Of the FQ-resistant isolates, three major FQ resistance mechanisms were investigated. Of the 59 isolates, plasmid-mediated quinolone resistance genes were detected in 9 isolates (15.3%). Efflux pump activity was found in 56 isolates (94.9%); however, this was not correlated with the increased FQ resistance measured by determining the MIC. Point mutations in quinolone resistance–determining regions were the main cause of FQ resistance. All 59 ciprofloxacin-resistant isolates had mutations in quinolone resistance–determining regions; of these 59 isolates, all (100%) had mutations in gyrA, 58 (98.3%) had mutations in parC, 22 (37.3%) had mutations in parE, and none had mutations in gyrB. The predominant mutation type was double mutation in gyrA (Ser83Leu plus mutation in aspartic acid 87), and all FQ-resistant isolates (except one) that had mutations in parC or parE also had double mutations in gyrA. Importantly, the frequencies of multidrug-resistant and extended-spectrum β-lactamase–producing E. coli were significantly higher in the high ciprofloxacin MIC group in this study. Compared with previous studies in Korea, the prevalence of FQ resistance and plasmid-mediated quinolone resistance genes had increased considerably in swine. Although the use of FQ as a feed additive is prohibited in Korea, use for self-treatment and therapeutic purposes has been increasing, which may be responsible for the higher FQ resistance rate observed in this study. Therefore, prudent use of FQ on animal farms is warranted to reduce the evolution of FQ-resistant bacteria in the animal industry.

scholarly journals High prevalence of antibiotic resistance in commensal Escherichia coli from healthy human sources in community settings

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emmanuel Nji ◽  
Joseph Kazibwe ◽  
Thomas Hambridge ◽  
Carolyn Alia Joko ◽  
Amma Aboagyewa Larbi ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Enteric Bacteria ◽  
Resistant Bacteria ◽  
Hospital Inpatient ◽  
Community Settings ◽  
Health Crisis ◽  
E Coli ◽  
Healthy Humans ◽  
High Prevalence

AbstractAntibiotic resistance is a global health crisis that requires urgent action to stop its spread. To counteract the spread of antibiotic resistance, we must improve our understanding of the origin and spread of resistant bacteria in both community and healthcare settings. Unfortunately, little attention is being given to contain the spread of antibiotic resistance in community settings (i.e., locations outside of a hospital inpatient, acute care setting, or a hospital clinic setting), despite some studies have consistently reported a high prevalence of antibiotic resistance in the community settings. This study aimed to investigate the prevalence of antibiotic resistance in commensal Escherichia coli isolates from healthy humans in community settings in LMICs. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we synthesized studies conducted from 1989 to May 2020. A total of 9363 articles were obtained from the search and prevalence data were extracted from 33 articles and pooled together. This gave a pooled prevalence of antibiotic resistance (top ten antibiotics commonly prescribed in LMICs) in commensal E. coli isolates from human sources in community settings in LMICs of: ampicillin (72% of 13,531 isolates, 95% CI: 65–79), cefotaxime (27% of 6700 isolates, 95% CI: 12–44), chloramphenicol (45% of 7012 isolates, 95% CI: 35–53), ciprofloxacin (17% of 10,618 isolates, 95% CI: 11–25), co-trimoxazole (63% of 10,561 isolates, 95% CI: 52–73), nalidixic acid (30% of 9819 isolates, 95% CI: 21–40), oxytetracycline (78% of 1451 isolates, 95% CI: 65–88), streptomycin (58% of 3831 isolates, 95% CI: 44–72), tetracycline (67% of 11,847 isolates, 95% CI: 59–74), and trimethoprim (67% of 3265 isolates, 95% CI: 59–75). Here, we provided an appraisal of the evidence of the high prevalence of antibiotic resistance by commensal E. coli in community settings in LMICs. Our findings will have important ramifications for public health policy design to contain the spread of antibiotic resistance in community settings. Indeed, commensal E. coli is the main reservoir for spreading antibiotic resistance to other pathogenic enteric bacteria via mobile genetic elements.

scholarly journals Role of the SOS Response in the Generation of Antibiotic Resistance In Vivo

2021 ◽  
Author(s):  
John K. Crane ◽  
Cassandra L. Alvarado ◽  
Mark D. Sutton
Keyword(s):  
Antibiotic Resistance ◽  
Rabbit Model ◽  
Sos Response ◽  
Antimicrobial Drugs ◽  
Mutator Phenotype ◽  
E Coli ◽  
Gram Positive Bacteria ◽  
Almost All

The SOS response to DNA damage is a conserved stress response in Gram-negative and Gram-positive bacteria. Although this pathway has been studied for years, its relevance is still not familiar to many working in the fields of clinical antibiotic resistance and stewardship. In some conditions, the SOS response favors DNA repair and preserves the genetic integrity of the organism. On the other hand, the SOS response also includes induction of error-prone DNA polymerases, which can increase the rate of mutation, called the mutator phenotype or “hypermutation.” As a result, mutations can occur in genes conferring antibiotic resistance, increasing the acquisition of resistance to antibiotics. Almost all of the work on the SOS response has been on bacteria exposed to stressors in vitro. In this study, we sought to quantitate the effects of the SOS-inducing drugs in vivo, in comparison with the same drugs in vitro. We used a rabbit model of intestinal infection with enteropathogenic E. coli, strain E22. SOS -inducing drugs triggered the mutator phenotype response in vivo as well as in vitro. Exposure of E. coli strain E22 to ciprofloxacin or zidovudine, both of which induce the SOS response in vitro, resulted in increased antibiotic resistance to 3 antibiotics: rifampin, minocycline, and fosfomycin. Zinc was able to inhibit SOS-induced emergence of antibiotic resistance in vivo, as previously observed in vitro. Our findings may have relevance in reducing emergence of resistance to new antimicrobial drugs.

scholarly journals Escaping from ESKAPE. Clinical Significance and Antibiotic Resistance Mechanisms in Acinetobacter baumannii: a Review

2020 ◽  
Vol 11 (1) ◽  
pp. 8190-8203
Keyword(s):  
Antibiotic Resistance ◽  
Acinetobacter Baumannii ◽  
Nosocomial Infections ◽  
Antimicrobial Agents ◽  
Genetic Resistance ◽  
Resistance Mechanisms ◽  
Genomic Islands ◽  
Resistant Bacteria ◽  
Clinical Settings

Antibiotic resistance represents a critical threat in clinical settings nowadays, with an essential ecological dimension. Due to the involvement of the resistance genes, this phenomenon has gained an unprecedented expansion. Their accumulation and dissemination are facilitated by mobile genetic elements (MGEs) (plasmids, transposons, integrons, genomic islands) that can increase intracellular DNA mobility. In clinical settings, one of the critical resistant bacteria associated with nosocomial infections is Acinetobacter baumannii. This Gram-negative bacterium exhibits variate resistance mechanisms that enable it to survive in extreme environmental conditions and to evade antimicrobial agents. The enormous adaptive capacity and the essential role in the emergence of severe nosocomial infections lead to the need to study more deeply the mechanisms involved in antibiotic resistance in A. baumannii strains. In this review, we will initially present the role of A. baumannii in human and veterinary infectious pathology. We will subsequently discuss the main genetic resistance mechanisms (both intrinsic and acquired) encountered in A. baumannii strains.

Relationship of antibiotic resistance to results of treatment in sepsis patients in Hue Central Hospital 2017 – 2018

2019 ◽  
pp. 48-54
Author(s):  
Duy Binh Nguyen ◽  
Trung Tien Phan ◽  
Trong Hanh Hoang ◽  
Van Tuan Mai ◽  
Xuan Chuong Tran
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infection ◽  
Resistant Bacteria ◽  
Central Hospital ◽  
International Consensus ◽  
Antibiotic Resistant ◽  
E Coli ◽  
Results Of Treatment ◽  
Amoxicillin Clavulanic Acid ◽  
Relationship Of

Sepsis is a serious bacterial infection. The main treatment is using antibiotics. However, the rate of antibiotic resistance is very high and this resistance is related to the outcome of treatment. Objectives: To evaluate the situation of antibiotic resistance of some isolated bacteria in sepsis patients treated at Hue Central Hospital; to evaluate the relationship of antibiotic resistance to the treatment results in patients with sepsis. Subjects and methods: prospective study of 60 sepsis patients diagnosed according to the criteria of the 3rd International Consensus-Sepsis 3 and its susceptibility patterns from April 2017 to August 2018. Results and Conclusions: The current agents of sepsis are mainly S. suis, Burkhoderiae spp. and E. coli. E. coli is resistant to cephalosporins 3rd, 4th generation and quinolone group is over 75%; resistance to imipenem 11.1%; the ESBL rate is 60%. S. suis resistant to ampicilline 11.1%; no resistance has been recorded to ceftriaxone and vancomycine. Resistance of Burkholderiae spp. to cefepime and amoxicillin/clavulanic acid was 42.9% and 55.6%, resistant to imipenem and meropenem is 20%, resistance to ceftazidime was not recorded. The deaths were mostly dued to E. coli and K. pneumoniae. The mortality for patients infected with antibiotic-resistant bacteria are higher than for sensitive groups. Key words: Sepsis, bacterial infection, antibiotics

Development of Peptides that Inhibit Aminoglycoside-Modifying Enzymes and β-Lactamases for Control of Resistant Bacteria

2020 ◽  
Vol 21 (10) ◽  
pp. 1011-1026
Author(s):  
Bruna O. Costa ◽  
Marlon H. Cardoso ◽  
Octávio L. Franco
Keyword(s):  
Drug Target ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Specific Chemical ◽  
Target Interaction ◽  
Multiresistant Bacteria ◽  
Acute Bacterial Infections

: Aminoglycosides and β-lactams are the most commonly used antimicrobial agents in clinical practice. This occurs because they are capable of acting in the treatment of acute bacterial infections. However, the effectiveness of antibiotics has been constantly threatened due to bacterial pathogens producing resistance enzymes. Among them, the aminoglycoside-modifying enzymes (AMEs) and β-lactamase enzymes are the most frequently reported resistance mechanisms. AMEs can inactivate aminoglycosides by adding specific chemical molecules in the compound, whereas β-lactamases hydrolyze the β-lactams ring, preventing drug-target interaction. Thus, these enzymes provide a scenario of multidrug-resistance and a significant threat to public health at a global level. In response to this challenge, in recent decades, several studies have focused on the development of inhibitors that can restore aminoglycosides and β-lactams activity. In this context, peptides appear as a promising approach in the field of inhibitors for future antibacterial therapies, as multiresistant bacteria may be susceptible to these molecules. Therefore, this review focused on the most recent findings related to peptide-based inhibitors that act on AMEs and β-lactamases, and how these molecules could be used for future treatment strategies.

scholarly journals Nitric oxide (NO) elicits aminoglycoside tolerance in Escherichia coli but antibiotic resistance gene carriage and NO sensitivity have not co-evolved

2021 ◽  
Author(s):  
Cláudia A. Ribeiro ◽  
Luke A. Rahman ◽  
Louis G. Holmes ◽  
Ayrianna M. Woody ◽  
Calum M. Webster ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Antibiotic Resistance ◽  
Antibiotic Susceptibility ◽  
Bacterial Pathogens ◽  
Antibiotic Resistance Gene ◽  
Antibiotic Resistance Genes ◽  
Resistance Mechanisms ◽  
Current Work ◽  
E Coli ◽  
Respiratory Inhibitor

AbstractThe spread of multidrug-resistance in Gram-negative bacterial pathogens presents a major clinical challenge, and new approaches are required to combat these organisms. Nitric oxide (NO) is a well-known antimicrobial that is produced by the immune system in response to infection, and numerous studies have demonstrated that NO is a respiratory inhibitor with both bacteriostatic and bactericidal properties. However, given that loss of aerobic respiratory complexes is known to diminish antibiotic efficacy, it was hypothesised that the potent respiratory inhibitor NO would elicit similar effects. Indeed, the current work demonstrates that pre-exposure to NO-releasers elicits a > tenfold increase in IC50 for gentamicin against pathogenic E. coli (i.e. a huge decrease in lethality). It was therefore hypothesised that hyper-sensitivity to NO may have arisen in bacterial pathogens and that this trait could promote the acquisition of antibiotic-resistance mechanisms through enabling cells to persist in the presence of toxic levels of antibiotic. To test this hypothesis, genomics and microbiological approaches were used to screen a collection of E. coli clinical isolates for antibiotic susceptibility and NO tolerance, although the data did not support a correlation between increased carriage of antibiotic resistance genes and NO tolerance. However, the current work has important implications for how antibiotic susceptibility might be measured in future (i.e. ± NO) and underlines the evolutionary advantage for bacterial pathogens to maintain tolerance to toxic levels of NO.

scholarly journals Resistance and Adaptation of Bacteria to Non-Antibiotic Antibacterial Agents: Physical Stressors, Nanoparticles, and Bacteriophages

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 435
Author(s):  
Sada Raza ◽  
Kinga Matuła ◽  
Sylwia Karoń ◽  
Jan Paczesny
Keyword(s):  
Antimicrobial Resistance ◽  
Antibacterial Agents ◽  
Uv Light ◽  
Resistance Mechanisms ◽  
Resistant Bacteria ◽  
Physical Factors ◽  
Defense Systems ◽  
Drug Resistant Bacteria

Antimicrobial resistance is a significant threat to human health worldwide, forcing scientists to explore non-traditional antibacterial agents to support rapid interventions and combat the emergence and spread of drug resistant bacteria. Many new antibiotic-free approaches are being developed while the old ones are being revised, resulting in creating unique solutions that arise at the interface of physics, nanotechnology, and microbiology. Specifically, physical factors (e.g., pressure, temperature, UV light) are increasingly used for industrial sterilization. Nanoparticles (unmodified or in combination with toxic compounds) are also applied to circumvent in vivo drug resistance mechanisms in bacteria. Recently, bacteriophage-based treatments are also gaining momentum due to their high bactericidal activity and specificity. Although the number of novel approaches for tackling the antimicrobial resistance crisis is snowballing, it is still unclear if any proposed solutions would provide a long-term remedy. This review aims to provide a detailed overview of how bacteria acquire resistance against these non-antibiotic factors. We also discuss innate bacterial defense systems and how bacteriophages have evolved to tackle them.

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