scholarly journals Frequency, Spectrum, and Nonzero Fitness Costs of Resistance to Myxopyronin in Staphylococcus aureus

2012 ◽  
Vol 56 (12) ◽  
pp. 6250-6255 ◽  
Author(s):  
Aashish Srivastava ◽  
David Degen ◽  
Yon W. Ebright ◽  
Richard H. Ebright
Keyword(s):  
Staphylococcus Aureus ◽  
Binding Site ◽  
Frequency Spectrum ◽  
Resistance Rate ◽  
Cross Resistance ◽  
Β Subunit ◽  
Fitness Costs ◽  
Switch Region ◽  
Content Type ◽  
Resistant Mutants

ABSTRACTThe antibiotic myxopyronin (Myx) functions by inhibiting bacterial RNA polymerase (RNAP). The binding site on RNAP for Myx—the RNAP “switch region SW1/SW2 subregion”—is different from the binding site on RNAP for the RNAP inhibitor currently used in broad-spectrum antibacterial therapy, rifampin (Rif). Here, we report the frequency, spectrum, and fitness costs of Myx resistance inStaphylococcus aureus. The resistance rate for Myx is 4 × 10−8to 7 × 10−8per generation, which is equal within error to the resistance rate for Rif (3 × 10−8to 10 × 10−8per generation). Substitutions conferring Myx resistance were obtained in the RNAP β subunit [six substitutions: V1080(1275)I, V1080(1275)L, E1084(1279)K, D1101(1296)E, S1127(1322)L, and S1127(1322)P] and the RNAP β′ subunit [five substitutions: K334(345)N, T925(917)K, T925(917)R, G1172(1354)C, and G1172(1354)D] (residues numbered as inStaphylococcus aureusRNAP and, in parentheses, as inEscherichia coliRNAP). Sites of substitutions conferring Myx resistance map to the RNAP switch region SW1/SW2 subregion and do not overlap the binding site on RNAP for Rif, and, correspondingly, Myx-resistant mutants exhibit no cross-resistance to Rif. All substitutions conferring Myx resistance exhibit significant fitness costs (4 to 15% per generation). In contrast, at least three substitutions conferring Rif resistance exhibit no fitness costs (≤0% per generation). The observation that all Myx-resistant mutants have significant fitness costs whereas at least three Rif-resistant mutants have no fitness costs, together with the previously established inverse correlation between fitness cost and clinical prevalence, suggests that Myx resistance is likely to have lower clinical prevalence than Rif resistance.

scholarly journals Insights into the Mechanism of Inhibition of Novel Bacterial Topoisomerase Inhibitors from Characterization of Resistant Mutants of Staphylococcus aureus

2015 ◽  
Vol 59 (9) ◽  
pp. 5278-5287 ◽  
Author(s):  
Sushmita D. Lahiri ◽  
Amy Kutschke ◽  
Kathy McCormack ◽  
Richard A. Alm
Keyword(s):  
Staphylococcus Aureus ◽  
Dna Gyrase ◽  
Cross Resistance ◽  
Type Ii ◽  
Topoisomerase Inhibitors ◽  
Topoisomerase Iv ◽  
Content Type ◽  
Mechanism Of Inhibition ◽  
Resistant Mutants ◽  
Dna Complex

ABSTRACTThe type II topoisomerases DNA gyrase and topoisomerase IV are clinically validated bacterial targets that catalyze the modulation of DNA topology that is vital to DNA replication, repair, and decatenation. Increasing resistance to fluoroquinolones, which trap the topoisomerase-DNA complex, has led to significant efforts in the discovery of novel inhibitors of these targets. AZ6142 is a member of the class of novel bacterial topoisomerase inhibitors (NBTIs) that utilizes a distinct mechanism to trap the protein-DNA complex. AZ6142 has very potent activity against Gram-positive organisms, includingStaphylococcus aureus,Streptococcus pneumoniae, andStreptococcus pyogenes. In this study, we determined the frequencies of resistance to AZ6142 and other representative NBTI compounds inS. aureusandS. pneumoniae. The frequencies of selection of resistant mutants at 4× the MIC were 1.7 × 10−8forS. aureusand <5.5 × 10−10forS. pneumoniae. To improve our understanding of the NBTI mechanism of inhibition, the resistantS. aureusmutants were characterized and 20 unique substitutions in the topoisomerase subunits were identified. Many of these substitutions were located outside the NBTI binding pocket and impact the susceptibility of AZ6142, resulting in a 4- to 32-fold elevation in the MIC over the wild-type parent strain. Data on cross-resistance with other NBTIs and fluoroquinolones enabled the differentiation of scaffold-specific changes from compound-specific variations. Our results suggest that AZ6142 inhibits both type II topoisomerases inS. aureusbut that DNA gyrase is the primary target. Further, the genotype of the resistant mutants suggests that domain conformations and DNA interactions may uniquely impact NBTIs compared to fluoroquinolones.

scholarly journals Emergence of Linezolid-Resistant Mutants in a Susceptible-Cell Population of Methicillin-Resistant Staphylococcus aureus

2011 ◽  
Vol 55 (5) ◽  
pp. 2466-2468 ◽  
Author(s):  
Yurika Ikeda-Dantsuji ◽  
Hideaki Hanaki ◽  
Taiji Nakae ◽  
Yoshio Takesue ◽  
Kazunori Tomono ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Population ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Rrna Genes ◽  
Chloramphenicol Resistance ◽  
Methicillin Resistant ◽  
Content Type ◽  
Susceptible Cell ◽  
Linezolid Therapy ◽  
Resistant Mutants

ABSTRACTMethicillin-resistantStaphylococcus aureuswith a MIC of linezolid of 4 μg/ml, isolated from a patient who had undergone unsuccessful linezolid therapy, yielded linezolid-resistant mutants in blood agar at 48 h of incubation. The resistant clones showed a MIC of linezolid ranging from 8 to 64 μg/ml and accumulated the T2500A mutation(s) of the rRNA genes. Emergence of these resistant clones appears to be facilitated by a cryptic mutation or mutations associated with chloramphenicol resistance.

scholarly journals A Mutation of RNA Polymerase β′ Subunit (RpoC) Converts Heterogeneously Vancomycin-Intermediate Staphylococcus aureus (hVISA) into “Slow VISA”

2015 ◽  
Vol 59 (7) ◽  
pp. 4215-4225 ◽  
Author(s):  
Miki Matsuo ◽  
Tomomi Hishinuma ◽  
Yuki Katayama ◽  
Keiichi Hiramatsu
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Rna Polymerase ◽  
Stringent Response ◽  
Whole Genome ◽  
Multicopy Plasmid ◽  
Β Subunit ◽  
Whole Genome Analysis ◽  
Content Type ◽  
Peptidoglycan Biosynthesis

ABSTRACTVarious mutations in therpoBgene, which encodes the RNA polymerase β subunit, are associated with increased vancomycin (VAN) resistance in vancomycin-intermediateStaphylococcus aureus(VISA) and heterogeneously VISA (hVISA) strains. We reported thatrpoBmutations are also linked to the expression of the recently found “slow VISA” (sVISA) phenotype (M. Saito, Y. Katayama, T. Hishinuma, A. Iwamoto, Y. Aiba, K Kuwahara-Arai, L. Cui, M. Matsuo, N. Aritaka, and K. Hiramatsu, Antimicrob Agents Chemother 58:5024–5035, 2014,http://dx.doi.org/10.1128/AAC.02470-13). Because RpoC and RpoB are components of RNA polymerase, we examined the effect of therpoC(P440L) mutation on the expression of the sVISA phenotype in the Mu3fdh2*V6-5 strain (V6-5), which was derived from a previously reported hVISA strain with the VISA phenotype. V6-5 had an extremely prolonged doubling time (DT) (72 min) and high vancomycin MIC (16 mg/liter). However, the phenotype of V6-5 was unstable, and the strain frequently reverted to hVISA with concomitant loss of low growth rate, cell wall thickness, and reduced autolysis. Whole-genome sequencing of phenotypic revertant strain V6-5-L1 and comparison with V6-5 revealed a second mutation, F562L, inrpoC. Introduction of the wild-type (WT)rpoCgene using a multicopy plasmid resolved the sVISA phenotype of V6-5, indicating that therpoC(P440L) mutant expressed the sVISA phenotype in hVISA. To investigate the mechanisms of resistance in the sVISA strain, we independently isolated an additional 10 revertants to hVISA and VISA. In subsequent whole-genome analysis, we identified compensatory mutations in the genes of three distinct functional categories: therpoCgene itself as regulatory mutations, peptidoglycan biosynthesis genes, andrelQ, which is involved in the stringent response. It appears that therpoC(P440L) mutation causes the sVISA phenotype by augmenting cell wall peptidoglycan synthesis and through the control of the stringent response.

scholarly journals RNA Polymerase Inhibitors with Activity against Rifampin-Resistant Mutants of Staphylococcus aureus

2000 ◽  
Vol 44 (11) ◽  
pp. 3163-3166 ◽  
Author(s):  
Alexander O'Neill ◽  
Brunello Oliva ◽  
Christopher Storey ◽  
Anthony Hoyle ◽  
Colin Fishwick ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Development ◽  
Rna Polymerase ◽  
Gene Mutations ◽  
Β Subunit ◽  
Polymerase Inhibitors ◽  
Resistant Mutants ◽  
Sorangicin A

ABSTRACT A collection of rifampin-resistant mutants of Staphylococcus aureus with characterized RNA polymerase β-subunit (rpoB) gene mutations was cross-screened against a number of other RNA polymerase inhibitors to correlate susceptibility with specific rpoB genotypes. The rpoB mutants were cross-resistant to streptolydigin and sorangicin A. In contrast, thiolutin, holomycin, corallopyronin A, and ripostatin A retained activity against the rpoB mutants. The second group of inhibitors may be of interest as drug development candidates.

scholarly journals Peptide Deformylase in Staphylococcus aureus: Resistance to Inhibition Is Mediated by Mutations in the Formyltransferase Gene

2000 ◽  
Vol 44 (7) ◽  
pp. 1825-1831 ◽  
Author(s):  
Peter S. Margolis ◽  
Corinne J. Hackbarth ◽  
Dennis C. Young ◽  
Wen Wang ◽  
Dawn Chen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Genomic Library ◽  
Specific Inhibitor ◽  
Peptide Deformylase ◽  
Cross Resistance ◽  
Loss Of Function ◽  
Wild Type ◽  
Chromosomal Dna ◽  
Resistant Mutants

ABSTRACT Peptide deformylase, a bacterial enzyme, represents a novel target for antibiotic discovery. Two deformylase homologs, defA and defB, were identified inStaphylococcus aureus. The defA homolog, located upstream of the transformylase gene, was identified by genomic analysis and was cloned from chromosomal DNA by PCR. A distinct homolog, defB, was cloned from an S. aureus genomic library by complementation of the arabinose-dependent phenotype of a P BAD -def Escherichia coli strain grown under arabinose-limiting conditions. Overexpression in E. coli of defB, but not defA, correlated to increased deformylase activity and decreased susceptibility to actinonin, a deformylase-specific inhibitor. ThedefB gene could not be disrupted in wild-type S. aureus, suggesting that this gene, which encodes a functional deformylase, is essential. In contrast, thedefA gene could be inactivated; the function of this gene is unknown. Actinonin-resistant mutants grew slowly in vitro and did not show cross-resistance to other classes of antibiotics. When compared to the parent, an actinonin-resistant strain produced an attenuated infection in a murine abscess model, indicating that this strain also has a growth disadvantage in vivo. Sequence analysis of the actinonin-resistant mutants revealed that each harbors a loss-of-function mutation in the fmt gene. Susceptibility to actinonin was restored when the wild-type fmt gene was introduced into these mutant strains. An S. aureusΔfmt strain was also resistant to actinonin, suggesting that a functional deformylase activity is not required in a strain that lacks formyltransferase activity. Accordingly, thedefB gene could be disrupted in an fmt mutant.

scholarly journals Inhibition of Staphylococcus aureus Cell Wall Biosynthesis by Desleucyl-Oritavancin: a Quantitative Peptidoglycan Composition Analysis by Mass Spectrometry

2017 ◽  
Vol 199 (15) ◽  
Author(s):  
James D. Chang ◽  
Erin E. Foster ◽  
Aanchal N. Thadani ◽  
Alejandro J. Ramirez ◽  
Sung Joon Kim
Keyword(s):  
Mass Spectrometry ◽  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Binding Site ◽  
Mode Of Action ◽  
Composition Analysis ◽  
Edman Degradation ◽  
Glycopeptide Antibiotics ◽  
Content Type ◽  
The Cross

ABSTRACT Oritavancin is a lipoglycopeptide antibiotic that exhibits potent activities against vancomycin-resistant Gram-positive pathogens. Oritavancin differs from vancomycin by a hydrophobic side chain attached to the drug disaccharide, which forms a secondary binding site to enable oritavancin binding to the cross-linked peptidoglycan in the cell wall. The mode of action of secondary binding site was investigated by measuring the changes in the peptidoglycan composition of Staphylococcus aureus grown in the presence of desleucyl-oritavancin at subinhibitory concentration using liquid chromatography-mass spectrometry (LC-MS). Desleucyl-oritavancin is an Edman degradation product of oritavancin that exhibits potent antibacterial activities despite the damaged d-Ala–d-Ala binding site due to its functional secondary binding site. Accurate quantitative peptidoglycan composition analysis based on 83 muropeptide ions determined that cell walls of S. aureus grown in the presence of desleucyl-oritavancin showed a reduction of peptidoglycan cross-linking, increased muropeptides with a tetrapeptide-stem structure, decreased O-acetylation of MurNAc, and increased N-deacetylation of GlcNAc. The changes in peptidoglycan composition suggest that desleucyl-oritavancin targets the peptidoglycan template to induce cell wall disorder and interferes with cell wall maturation. IMPORTANCE Oritavancin is a lipoglycopeptide antibiotic with a secondary binding site that targets the cross-linked peptidoglycan bridge structure in the cell wall. Even after the loss of its primary d-Ala–d-Ala binding site through Edman degradation, desleucyl-oritavancin exhibits potent antimicrobial activities through its still-functioning secondary binding site. In this study, we characterized the mode of action for desleucyl-oritavancin's secondary binding site using LC-MS. Peptidoglycan composition analysis of desleucyl-oritavancin-treated S. aureus was performed by determining the relative abundances of 83 muropeptide ions matched from a precalculated library through integrating extracted ion chromatograms. Our work highlights the use of quantitative peptidoglycan composition analysis by LC-MS to provide insights into the mode of action of glycopeptide antibiotics.

scholarly journals High-Level Pacidamycin Resistance in Pseudomonas aeruginosa Is Mediated by an Opp Oligopeptide Permease Encoded by theopp-fabIOperon

2013 ◽  
Vol 57 (11) ◽  
pp. 5565-5571 ◽  
Author(s):  
Anita Mistry ◽  
Mark S. Warren ◽  
John K. Cusick ◽  
RoxAnn R. Karkhoff-Schweizer ◽  
Olga Lomovskaya ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
High Frequency ◽  
Cross Resistance ◽  
Peptide Antibiotics ◽  
Content Type ◽  
Resistant Mutants ◽  
High Level ◽  
Level Resistance ◽  
Resistance Mutants

ABSTRACTPacidamycins (or uridyl peptide antibiotics) possess selectivein vivoactivity againstPseudomonas aeruginosa. An important limitation for the therapeutic use of pacidamycins withP. aeruginosais the high frequency (10−6to 10−7) at which resistant mutants emerge. To elucidate the mechanism(s) of this resistance, pacidamycin-resistantP. aeruginosamutants were isolated. Two types of mutants were obtained. Type 1, or high-level resistance mutants with a pacidamycin MIC of 512 μg/ml, were more abundant, with a frequency of ∼2 × 10−6, and did not show cross-resistance with other antibiotics. Type 2, low-level resistance mutants, were isolated with a frequency of ∼10−8and had a pacidamycin MIC of 64 μg/ml (the MIC for the wild-type strain was 4 to 16 μg/ml). These mutants were cross-resistant to levofloxacin, tetracycline, and erythromycin and were shown to overexpress either the MexAB-OprM or MexCD-OprJ multidrug resistance efflux pumps. High-level resistant mutants were isolated by transposon mutagenesis and one insertion was localized tooppB, one of two periplasmic binding protein components of an oligopeptide transport system which is encoded by theopp-fabIoperon. The Opp system is required for uptake of pacidamycin across the inner membrane, since variousopp, but notfabI, mutants were resistant to high levels of pacidamycin. Both of the two putative Opp periplasmic binding proteins, OppA and OppB, were required for pacidamycin uptake. Although both impaired uptake into and efflux from the cell can cause pacidamycin resistance inP. aeruginosa, our data suggest that impaired uptake is the primary reason for the high-frequency and high-level pacidamycin resistance.

scholarly journals The Neutrally Charged Diarylurea Compound PQ401 Kills Antibiotic-Resistant and Antibiotic-Tolerant Staphylococcus aureus

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Wooseong Kim ◽  
Guijin Zou ◽  
Wen Pan ◽  
Nico Fricke ◽  
Hammad A. Faizi ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Lipid Bilayers ◽  
Antimicrobial Agents ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Lead Compound ◽  
Neutral Form ◽  
Cationic Form ◽  
Antibiotic Resistant ◽  
Content Type

ABSTRACT Resistance or tolerance to traditional antibiotics is a challenging issue in antimicrobial chemotherapy. Moreover, traditional bactericidal antibiotics kill only actively growing bacterial cells, whereas nongrowing metabolically inactive cells are tolerant to and therefore “persist” in the presence of legacy antibiotics. Here, we report that the diarylurea derivative PQ401, previously characterized as an inhibitor of the insulin-like growth factor I receptor, kills both antibiotic-resistant and nongrowing antibiotic-tolerant methicillin-resistant Staphylococcus aureus (MRSA) by lipid bilayer disruption. PQ401 showed several beneficial properties as an antimicrobial lead compound, including rapid killing kinetics, low probability for resistance development, high selectivity to bacterial membranes compared to mammalian membranes, and synergism with gentamicin. In contrast to well-studied membrane-disrupting cationic antimicrobial low-molecular-weight compounds and peptides, molecular dynamic simulations supported by efficacy data demonstrate that the neutral form of PQ401 penetrates and subsequently embeds into bacterial lipid bilayers more effectively than the cationic form. Lastly, PQ401 showed efficacy in both the Caenorhabditis elegans and Galleria mellonella models of MRSA infection. These data suggest that PQ401 may be a lead candidate for repurposing as a membrane-active antimicrobial and has potential for further development as a human antibacterial therapeutic for difficult-to-treat infections caused by both drug-resistant and -tolerant S. aureus. IMPORTANCE Membrane-damaging antimicrobial agents have great potential to treat multidrug-resistant or multidrug-tolerant bacteria against which conventional antibiotics are not effective. However, their therapeutic applications are often hampered due to their low selectivity to bacterial over mammalian membranes or their potential for cross-resistance to a broad spectrum of cationic membrane-active antimicrobial agents. We discovered that the diarylurea derivative compound PQ401 has antimicrobial potency against multidrug-resistant and multidrug-tolerant Staphylococcus aureus. PQ401 selectively disrupts bacterial membrane lipid bilayers in comparison to mammalian membranes. Unlike cationic membrane-active antimicrobials, the neutral form of PQ401 rather than its cationic form exhibits maximum membrane activity. Overall, our results demonstrate that PQ401 could be a promising lead compound that overcomes the current limitations of membrane selectivity and cross-resistance. Also, this work provides deeper insight into the design and development of new noncharged membrane-targeting therapeutics to combat hard-to-cure bacterial infections.

scholarly journals Rapid Emergence and Evolution of Staphylococcus aureus Clones HarboringfusC-Containing Staphylococcal Cassette Chromosome Elements

2016 ◽  
Vol 60 (4) ◽  
pp. 2359-2365 ◽  
Author(s):  
Sarah L. Baines ◽  
Benjamin P. Howden ◽  
Helen Heffernan ◽  
Timothy P. Stinear ◽  
Glen P. Carter ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Fusidic Acid ◽  
Molecular Mechanisms ◽  
Population Based ◽  
Resistance Rate ◽  
Content Type ◽  
Fitness Advantage ◽  
Genotypic Association ◽  
Rapid Emergence ◽  
Staphylococcal Cassette Chromosome

ABSTRACTThe prevalence of fusidic acid (FA) resistance amongStaphylococcus aureusstrains in New Zealand (NZ) is among the highest reported globally, with a recent study describing a resistance rate of approximately 28%. Three FA-resistantS. aureusclones (ST5 MRSA, ST1 MSSA, and ST1 MRSA) have emerged over the past decade and now predominate in NZ, and in all three clones FA resistance is mediated by thefusCgene. In particular, ST5 MRSA has rapidly become the dominant MRSA clone in NZ, although the origin of FA-resistant ST5 MRSA has not been explored, and the genetic context offusCin FA-resistant NZ isolates is unknown. To better understand the rapid emergence of FA-resistantS. aureus, we used population-based comparative genomics to characterize a collection of FA-resistant and FA-susceptible isolates from NZ. FA-resistant NZ ST5 MRSA displayed minimal genetic diversity and represented a phylogenetically distinct clade within a global population model of clonal complex 5 (CC5)S. aureus. In all lineages,fusCwas invariably located within staphylococcal cassette chromosome (SCC) elements, suggesting that SCC-mediated horizontal transfer is the primary mechanism offusCdissemination. The genotypic association offusCwithmecAhas important implications for the emergence of MRSA clones in populations with high usage of fusidic acid. In addition, we found thatfusCwas colocated with a recently described virulence factor (tirS) in dominant NZS. aureusclones, suggesting a fitness advantage. This study points to the likely molecular mechanisms responsible for the successful emergence and spread of FA-resistantS. aureus.

scholarly journals Heterogeneity ofmprFSequences in Methicillin-Resistant Staphylococcus aureus Clinical Isolates: Role in Cross-Resistance between Daptomycin and Host Defense Antimicrobial Peptides

2014 ◽  
Vol 58 (12) ◽  
pp. 7462-7467 ◽  
Author(s):  
Arnold S. Bayer ◽  
Nagendra N. Mishra ◽  
George Sakoulas ◽  
Poochit Nonejuie ◽  
Cynthia C. Nast ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Defense ◽  
Hot Spot ◽  
Cross Resistance ◽  
Phospholipid Content ◽  
Nucleotide Polymorphisms ◽  
Gain Of Function ◽  
Host Defense Peptides ◽  
Methicillin Resistant ◽  
Content Type

ABSTRACTOver the past several years, single-nucleotide polymorphisms (SNPs) within themprFopen reading frame (ORF) have been proposed to be associated with a gain-of-function phenotype in terms of daptomycin (DAP) nonsusceptibility (referred to as daptomycin resistance [DAP-R] herein for ease of presentation) inStaphylococcus aureus. We investigated the frequencies of SNPs within themprFORF and the relationships of such SNPs to cross-resistance between DAP and cationic host defense peptides (HDPs). Thirty-five well-characterized, unique DAP-susceptible (DAP-S) and DAP-R methicillin-resistantS. aureus(MRSA) isolates of the clonal complex 5 genotype were used. In addition tomprFSNPs and DAP-HDP cross-resistance, several other key genotypic and phenotypic metrics often associated with DAP-R were delineated, as follows: (i)mprFexpression, (ii) membrane phospholipid content, (iii) positive surface charge, (iv) DAP binding, and (v) cell wall thickness profiles. A number of DAP-S strains (MICs of ≤1 μg/ml) exhibitedmprFSNPs, occasionally with high-levelmprFsequence variation from the genotype reference strain. However, none of these SNPs were localized to well-chronicledmprFhot spot locations associated with DAP-R inS. aureus. In contrast, all 8 DAP-R isolates demonstrated SNPs within such knownmprFhot spots. Moreover, only the DAP-R strains showed MprF gain-of-function phenotypes, enhancedmprFexpression, higher survival against two prototypical HDPs, and reduced DAP binding. Although a heterogenous array ofmprFSNPs were often found in DAP-S strains, only selected hot spot SNPs, combined with concurrentmprFdysregulation, were associated with the DAP-R phenotype.

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