scholarly journals Full-Genome Sequencing Identifies in the Genetic Background Several Determinants That Modulate the Resistance Phenotype in Methicillin-Resistant Staphylococcus aureus Strains Carrying the Novel mecC Gene

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Catarina Milheiriço ◽  
Hermínia de Lencastre ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Genetic Background ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Content Type ◽  
Resistance Phenotype ◽  
Beta Lactam Antibiotics ◽  
Oxacillin Resistance ◽  
Mrsa Strains

ABSTRACT Most methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to beta-lactam antibiotics due to the presence of the mecA gene, encoding an extra penicillin-binding protein (PBP2A) that has low affinity for virtually all beta-lactam antibiotics. Recently, a new resistance determinant—the mecC gene—was identified in S. aureus isolates recovered from humans and dairy cattle. Although having typically low MICs to beta-lactam antibiotics, MRSA strains with the mecC determinant are also capable of expressing high levels of oxacillin resistance when in an optimal genetic background. In order to test the impact of extensive beta-lactam selection on the emergence of mecC-carrying strains with high levels of antibiotic resistance, we exposed the prototype mecC-carrying MRSA strain, LGA251, to increasing concentrations of oxacillin. LGA251 was able to rapidly adapt to high concentrations of oxacillin in growth medium. In such laboratory mutants with increased levels of oxacillin resistance, we identified mutations in genes with no relationship to the mecC regulatory system, indicating that the genetic background plays an important role in the establishment of the levels of oxacillin resistance. Our data also indicate that the stringent stress response plays a critical role in the beta-lactam antibiotic resistance phenotype of MRSA strains carrying the mecC determinant.

scholarly journals Role of the Stringent Stress Response in the Antibiotic Resistance Phenotype of Methicillin-Resistant Staphylococcus aureus

2016 ◽  
Vol 60 (4) ◽  
pp. 2311-2317 ◽  
Author(s):  
Sandra Aedo ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Stress Response ◽  
Phenotypic Expression ◽  
Beta Lactam ◽  
Resistance Level ◽  
Methicillin Resistant ◽  
Content Type ◽  
Resistance Phenotype ◽  
Oxacillin Resistance ◽  
The Impact

ABSTRACTResistance to beta-lactam antibiotics in methicillin-resistantStaphylococcus aureus(MRSA) requires the presence of an acquired genetic determinant,mecAormecC, which encode penicillin-binding protein PBP2A or PBP2A′, respectively. Although all MRSA strains share a mechanism of resistance, the phenotypic expression of beta-lactam resistance shows considerable strain-to-strain variation. The stringent stress response, a stress response that results from nutrient limitation, was shown to play a key role in determining the resistance level of an MRSA strain. In the present study, we validated the impact of the stringent stress response on transcription and translation ofmecAin the MRSA clinical isolate strain N315, which also carries known regulatory genes (mecI/mecR1/mecR2andblaI/blaR1) formecAtranscription. We showed that the impact of the stringent stress response on the resistance level may be restricted to beta-lactam resistance based on a “foreign” determinant such asmecA, as opposed to resistance based on mutations in the nativeS. aureusdeterminantpbpB(encoding PBP2). Our observations demonstrate that high-level resistance mediated by the stringent stress response follows the current model of beta-lactam resistance in which the native PBP2 protein is also essential for expression of the resistance phenotype. We also show that theStaphylococcus sciuri pbpDgene (also calledmecAI), the putative evolutionary precursor ofmecA, confers oxacillin resistance in anS. aureusstrain, generating a heterogeneous phenotype that can be converted to high and homogenous resistance by induction of the stringent stress response in the bacteria.

Genomic Overview into the Evolving Epidemiology of Methicillin-Resistant Staphylococcus aureus

2020 ◽  
Vol 21 (3) ◽  
pp. 125-131
Author(s):  
Yara El dessouky ◽  
Shaimaa Mouftah ◽  
Mohamed Elhadidy
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Human Infection ◽  
Emerging Infections ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Gram Positive Bacteria ◽  
Beta Lactam Antibiotics ◽  
Mrsa Strains ◽  
Hospital Acquired

Emerging infections represent an enormous challenge to both human and veterinary medicine. Identification of Methicillin-Resistant Staphylococcus aureus (MRSA) in various species and in food has raised concerns about the roles of animals in the epidemiology of MRSA. MRSA are a group of gram-positive bacteria, distinct from other strains of S. aureus in that this pathogen is resistant to methicillin, oxacillin, and all beta-lactam antibiotics. The severity of infections caused by MRSA depends on the strain responsible for the infection and can vary from soft tissue infections to bacteremia and sometimes pneumonia. MRSA strains are divided into clones, based on their genetic makeup. According to the setting of infection, MRSA are divided into three epidemiological types: hospital acquired (HA-MRSA), community acquired (CA-MRSA), and livestock acquired (LA-MRSA) (ie. Transmitted from animal carriers). The epidemiology of HA-MRSA, CA-MRSA, and LA-MRSA is blurred as different recent genetic studies have revealed significant overlap of identical clones between HA-MRSA and CA-MRSA, and the significant increase of human infection caused by LA-MRSA. Furthermore, the animal-human and animal-animal transmission of LA-MRSA has prompted further investigation to study the origin of this epidemiological type and the transmission dynamics. The genetic and virulence profiles of different types of MRSA vary widely, where community acquired and livestock acquired strains are more virulent than hospital acquired strains. This review sheds light on three epidemiological groups of MRSA (HA-MRSA, CA-MRSA, and LA-MRSA), and their most prevalent clonal clusters, that can consequently allow better understanding of their evolution, emergence, transmission, and global dissemination.

scholarly journals Rates of Carriage of Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus in an Outpatient Population

2003 ◽  
Vol 24 (6) ◽  
pp. 439-444 ◽  
Author(s):  
Julie Kenner ◽  
Tasha O'Connor ◽  
Nicholas Piantanida ◽  
Joel Fishbain ◽  
Bardwell Eberly ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Risk Factor ◽  
Clinical Risk Factor ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Beta Lactam Antibiotics ◽  
Time Period ◽  
Clinical Illness ◽  
Mrsa Strains ◽  
Mrsa Colonization

AbstractObjectives:To assess the prevalence of and the clinical features associated with asymptomatic Staphylococcus aureus colonization in a healthy outpatient population, and to compare the characteristics of colonizing methicillin-resistant S. aureus (MRSA) strains with those of strains causing infection in our community and hospital.Setting:Outpatient military clinics.Methods:Specimens were obtained from the nares, pharynx, and axillae of 404 outpatients, and a questionnaire was administered to obtain demographic and risk factor information. MRSA strains were typed by pulsed-field gel electrophoresis (PFGE) and evaluated for antibiotic susceptibility. Antibiograms of study MRSA strains were compared with those of MRSA strains causing clinical illness during the same time period.Results:Methicillin-susceptible S. aureus (MSSA) colonization was present in 153 (38%) of the 404 asymptomatic outpatients, and MRSA colonization was present in 8 (2%). Detection of colonization was highest from the nares. No clinical risk factor was significantly associated with MRSA colonization; however, a tendency was noted for MRSA to be more common in men and in those who were older or who had been recently hospitalized. All colonizing MRSA strains had unique patterns on PFGE. In contrast to strains responsible for hospital infections, most colonizing isolates of MRSA were susceptible to oral antibiotics.Conclusions:MRSA and MSSA colonization is common in our outpatient population. Colonization is best detected by nares cultures and most carriers of MRSA are without apparent predisposing risk factors for acquisition. Colonizing isolates of MRSA are heterogeneous and, unlike nosocomial isolates, often retain susceptibility to other non-beta-lactam antibiotics.

scholarly journals β-Lactams Increase the Antibacterial Activity of Daptomycin against Clinical Methicillin-Resistant Staphylococcus aureus Strains and Prevent Selection of Daptomycin-Resistant Derivatives

2012 ◽  
Vol 56 (12) ◽  
pp. 6192-6200 ◽  
Author(s):  
Shrenik Mehta ◽  
Christopher Singh ◽  
Konrad B. Plata ◽  
Palas K. Chanda ◽  
Arundhati Paul ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mutant Selection ◽  
Methicillin Resistant ◽  
Content Type ◽  
Oxacillin Resistance ◽  
Worm Model ◽  
Mrsa Strains ◽  
Selection Of

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) has emerged to be one of the most important pathogens both in health care and in community-onset infections. Daptomycin (DAP) is a cyclic anionic lipopeptide recommended for treatment of skin infections, bacteremia, and right-sided endocarditis caused by MRSA. Resistance to DAP (DAPr) has been reported in MRSA and is mostly accompanied by a parallel decrease in oxacillin resistance, a process known as the “seesaw effect.” Our study provides evidence that the seesaw effect applies to other β-lactams and carbapenems of clinical use, including nafcillin (NAF), cefotaxime (CTX), amoxicillin-clavulanic (AMC), and imipenem (IMP), in heterogeneous DAPrMRSA strains but not in MRSA strains expressing homogeneous β-lactam resistance. The antibacterial efficacy of DAP in combination with β-lactams was evaluated in isogenic DAP-susceptible (DAPs)/DaprMRSA strains originally obtained from patients that failed DAP monotherapy. Bothin vitro(MIC, synergy-kill curve) andin vivo(wax worm model) approaches were used. In these models, DAP and a β-lactam proved to be highly synergistic against both heterogeneous and homogeneous clinical DAPrMRSA strains. Mechanistically, β-lactams induced a reduction in the cell net positive surface charge, reverting the increased repulsion provoked by DAP alone, an effect that may favor the binding of DAP to the cell surface. The ease ofin vitromutant selection was observed when DAPsMRSA strains were exposed to DAP. Importantly, the combination of DAP and a β-lactam prevented the selection of DAPrvariants. In summary, our data show that the DAP–β-lactam combination may significantly enhance both thein vitroandin vivoefficacy of anti-MRSA therapeutic options against DAPrMRSA infections and represent an option in preventing DAPrselection in persistent or refractory MRSA infections.

scholarly journals Genetic Determinants of High-Level Oxacillin Resistance in Methicillin-Resistant Staphylococcus aureus

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Maria Pardos de la Gandara ◽  
Vitor Borges ◽  
Marilyn Chung ◽  
Catarina Milheiriço ◽  
João Paulo Gomes ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Phenotypic Expression ◽  
Beta Lactam ◽  
Genetic Determinants ◽  
Methicillin Resistant ◽  
Content Type ◽  
Clonal Type ◽  
Oxacillin Resistance ◽  
Resistant Phenotype ◽  
Six Genes

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains carry either a mecA - or a mecC -mediated mechanism of resistance to beta-lactam antibiotics, and the phenotypic expression of resistance shows extensive strain-to-strain variation. In recent communications, we identified the genetic determinants associated with the stringent stress response that play a major role in the antibiotic resistant phenotype of the historically earliest “archaic” clone of MRSA and in the mecC -carrying MRSA strain LGA251. Here, we sought to test whether or not the same genetic determinants also contribute to the resistant phenotype of highly and homogeneously resistant (H*R) derivatives of a major contemporary MRSA clone, USA300. We found that the resistance phenotype was linked to six genes ( fruB , gmk , hpt , purB , prsA , and relA ), which were most frequently targeted among the analyzed 20 H*R strains (one mutation per clone in 19 of the 20 H*R strains). Besides the strong parallels with our previous findings (five of the six genes matched), all but one of the repeatedly targeted genes were found to be linked to guanine metabolism, pointing to the key role that this pathway plays in defining the level of antibiotic resistance independent of the clonal type of MRSA.

scholarly journals Phenotypic Detection of Hemin-Inducible Trimethoprim-Sulfamethoxazole Heteroresistance in Staphylococcus aureus

2021 ◽  
Author(s):  
Dennis Nurjadi ◽  
Quan Chanthalangsy ◽  
Elfi Zizmann ◽  
Vanessa Stuermer ◽  
Maximilian Moll ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Clinical Medicine ◽  
Beta Lactam ◽  
Methicillin Resistant ◽  
Content Type ◽  
Therapeutic Challenge ◽  
Beta Lactam Antibiotics ◽  
Emergence Of Resistance ◽  
Antibiotic Agents

Staphylococcus aureus is one of most important pathogens in clinical medicine. Besides its virulence, the acquisition or emergence of resistance toward antibiotic agents, in particular to beta-lactam antibiotics (methicillin-resistant S. aureus [MRSA]), poses a major therapeutic challenge.

The role of mprF mutations in “see-saw effect” of Daptomycin-resistant methicillin-resistant Staphylococcus aureus isolates

2021 ◽  
Author(s):  
Shengnan Jiang ◽  
Hemu Zhuang ◽  
Feiteng Zhu ◽  
Xiang Wei ◽  
Junxiong Zhang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Novel Mutation ◽  
Point Mutations ◽  
Synergistic Activity ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Methicillin Resistant ◽  
Beta Lactam Antibiotics ◽  
Mrsa Strains ◽  
The Impact

The emergence of daptomycin-resistant (DAP-R) Staphylococcus aureus strains has become a global problem. Point mutations in mprF are the main cause of daptomycin (DAP) treatment failure. However, the impact of these specific point-mutations in methicillin-resistant S. aureus (MRSA) strains associated with DAP resistance and the “see-saw effect” of distinct beta-lactams remains unclear. In this study, we used three series of clinical MRSA strains with three distinct mutated mprF alleles from clone complexes (CC) 5 and 59 to explore the “see-saw effect” and the combination effect of DAP plus beta-lactams. Through construction of mprF deletion and complementation strains of SA268, we determined that mprF -S295A, mprF -S337L and one novel mutation of mprF- I348del within the bifunctional domain lead to DAP resistance. Compared with wild-type mprF cloned from a DAP-susceptible (DAP-S) strain, these three mprF mutations conferred the “see-saw effect” to distinct beta-lactams in the SA268Δ mprF strains and mutated- mprF (I348del and S337L) did not alter the cell surface positive charge ( P > 0.05). The susceptibility to beta-lactams increased significantly in DAP-R CC59 strains and the “see-saw effect” was found to be associated with distinct mutated mprF alleles and the category of beta-lactams. The synergistic activity of DAP plus oxacillin was detected in all DAP-R MRSA strains. Continued progress in understanding the mechanism of restoring susceptibility to beta-lactam antibiotics mediated by the mprF mutation and its impact on beta-lactam combination therapy will provide fundamental insights into treatment of MRSA infections.

scholarly journals Methicillin-Resistant Staphylococcus aureus in Hospitals: Latest Trends and Treatments Based on Bacteriophages

2019 ◽  
Vol 57 (12) ◽  
Author(s):  
Andrea Álvarez ◽  
Lucía Fernández ◽  
Diana Gutiérrez ◽  
Beatriz Iglesias ◽  
Ana Rodríguez ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Pathogenic Bacteria ◽  
World Health ◽  
Natural Phenomenon ◽  
Methicillin Resistant ◽  
Content Type ◽  
Wide Range ◽  
Mrsa Strains ◽  
Health Organization

ABSTRACT Even though antibiotic resistance in bacteria is a natural phenomenon, the alarming increase in pathogenic bacteria refractory to a wide range of antimicrobials is attracting attention worldwide. Indeed, the World Health Organization (WHO) has recently published a list of priority pathogens for which new antimicrobial alternatives are urgently needed. Among these pathogens, methicillin-resistant Staphylococcus aureus (MRSA) strains are perhaps the best known by the general public. In addition to its potential to acquire antibiotic resistance, S. aureus can produce a large number of virulence factors, such as hemolysins, enterotoxins, and proteases, and exhibits the ability to form biofilms as well as to evolve into different clones that can spread and colonize new environments. This review provides a brief overview of the latest options in antibacterial therapies, mainly focusing on phage therapy. In this regard, the current stage of research about antimicrobial compounds based on bacteriophages and endolysins against MRSA infections is shown and discussed.

scholarly journals Antibiotic Resistance as a Stress Response: Recovery of High-Level Oxacillin Resistance in Methicillin-Resistant Staphylococcus aureus “Auxiliary” (fem) Mutants by Induction of the Stringent Stress Response

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Choon Keun Kim ◽  
Catarina Milheiriço ◽  
Hermínia de Lencastre ◽  
Alexander Tomasz
Keyword(s):  
Staphylococcus Aureus ◽  
Antibiotic Resistance ◽  
Stress Response ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Penicillin Binding Protein ◽  
Methicillin Resistant ◽  
Content Type ◽  
Oxacillin Resistance ◽  
Response Recovery ◽  
High Level

ABSTRACT Studies with methicillin-resistant Staphylococcus aureus (MRSA) strain COL have shown that the optimal resistance phenotype requires not only mecA but also a large number of “auxiliary genes” identified by Tn551 mutagenesis. The majority of auxiliary mutants showed greatly increased levels of oxacillin resistance when grown in the presence of sub-MICs of mupirocin, suggesting that the mechanism of reduced resistance in the auxiliary mutants involved the interruption of a stringent stress response, causing reduced production of penicillin-binding protein 2A (PBP 2A).

scholarly journals Evaluation of Ceftaroline Alone and in Combination against Biofilm-Producing Methicillin-Resistant Staphylococcus aureus with Reduced Susceptibility to Daptomycin and Vancomycin in anIn VitroPharmacokinetic/Pharmacodynamic Model

2015 ◽  
Vol 59 (8) ◽  
pp. 4497-4503 ◽  
Author(s):  
Katie E. Barber ◽  
Jordan R. Smith ◽  
Cortney E. Ireland ◽  
Blaise R. Boles ◽  
Warren E. Rose ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Medical Device ◽  
Bloodstream Infections ◽  
Methicillin Resistant ◽  
Content Type ◽  
Elimination Half ◽  
Antimicrobial Protection ◽  
Mrsa Strains ◽  
Post Hoc

ABSTRACTAnnually, medical device infections are associated with >250,000 catheter-associated bloodstream infections (CLABSI), with up to 25% mortality.Staphylococcus aureus, a primary pathogen in these infections, is capable of biofilm production, allowing organism persistence in harsh environments, offering antimicrobial protection. With increases inS. aureusisolates with reduced susceptibility to current agents, ceftaroline (CPT) offers a therapeutic alternative. Therefore, we evaluated whether CPT would have a role against biofilm-producing methicillin-resistantS. aureus(MRSA), including those with decreased susceptibilities to alternative agents. In this study, we investigated CPT activity alone or combined with daptomycin (DAP) or rifampin (RIF) against 3 clinical biofilm-producing MRSA strains in anin vitrobiofilm pharmacokinetic/pharmacodynamic (PK/PD) model. Simulated antimicrobial regimens were as follows: 600 mg of CPT every 8 h (q8h) (free maximum concentration of drug [fCmax], 17.04 mg/liter; elimination half-life [t1/2], 2.66 h), 12 mg/kg of body weight/day of DAP (fCmax, 14.7 mg/liter;t1/2, 8 h), and 450 mg of RIF q12h (fCmax, 3.5 mg/liter;t1/2, 3.4 h), CPT plus DAP, and CPT plus RIF. Samples were obtained and plated to determine colony counts. Differences in log10CFU/cm2were evaluated by analysis of variance with Tukey'spost hoctest. The strains were CPT and vancomycin susceptible and DAP nonsusceptible (DNS). CPT displayed activity throughout the experiment. DAP demonstrated initial activity with regrowth at 24 h in all strains. RIF was comparable to the drug-free control, and little benefit was observed when combined with CPT. CPT plus DAP displayed potent activity, with an average log10CFU/cm2reduction of 3.33 ± 1.01 from baseline. CPT demonstrated activity against biofilm-producing DNS MRSA. CPT plus DAP displayed therapeutic enhancement over monotherapy, providing a potential option for difficult-to-treat medical device infections.

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