scholarly journals Interplay between meropenem and human serum albumin on expression of carbapenem resistance genes and natural competence in Acinetobacter baumannii

2021 ◽  
Author(s):  
Casin Le ◽  
Camila Pimentel ◽  
Marisel R. Tuttobene ◽  
Tomas Subils ◽  
Brent Nishimura ◽  
...  
Keyword(s):  
Human Serum ◽  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Natural Transformation ◽  
Expression Levels ◽  
Carbapenem Resistant ◽  
Synergistic Enhancement ◽  
Expression Of Genes ◽  
Foreign Dna ◽  
Accelerate Evolution

Acinetobacter baumannii A118, a mostly susceptible strain and AB5075, carbapenem-resistant, were cultured in Lysogeny broth (LB) or LB with different supplements: 3.5% human serum albumin (HSA), human serum (HS), meropenem, or meropenem plus 3.5% HSA. Natural transformation levels were enhanced in A. baumannii A118 and AB5075 cultured in medium supplemented with 3.5% HSA. Addition of meropenem plus 3.5% HSA caused synergistic enhancement of natural transformation in A. baumannii A118. Medium containing 3.5% HSA or meropenem enhanced the expression levels of the competence and type IV pilus associated genes. The combination meropenem plus 3.5% HSA produced a synergistic enhancement in the expression levels of many of these genes. The addition of HS, which has a high content of HSA, was also an inducer of these genes. Cultures grown in medium supplemented with HS or 3.5% HSA also affected resistance genes, which were expressed at higher or lower levels depending on the modification required to enhance resistance. The inducing or repressing activity of these modulators also occurred in three more carbapenem-resistant strains tested. An exception was the A. baumannii AMA16 bla NDM-1 gene, which was repressed in the presence of 3.5% HSA. In conclusion, HSA produces an enhancement of natural transformation and a modification in expression levels of competence genes and antibiotic resistance. Furthermore, when HSA is combined with carbapenems, which may increase the stress response, the expression of genes involved in natural competence is increased in A. baumannii . This process may favor the acquisition of foreign DNA and accelerate evolution. Importance Acinetobacter baumannii causes a variety of nosocomial- and community-infections that are usually resistant to multiple antimicrobial agents. As new strains acquire more resistance genes, these infections become more difficult to treat and mortality can reach up to 39%. The high genomic plasticity exhibited by A. baumannii must be the consequence of numerous mechanisms that include acquiring foreign DNA and recombination. Here, we describe the ability of A. baumannii to induce competence genes when exposed to environments that resemble those found in the human body during untreated infection or after administration of carbapenems. In this latter scenario expression of genes related to resistance also modify their expression levels such that resistance is increased. The contributions of this article are two-fold. Firstly, when A. baumannii is exposed to products present during infection, it responds, augmenting the ability to capture DNA and accelerate evolution. Secondly, in those conditions, the bacterium also modifies the expression of resistance genes to increase its resistance levels. In summary, recognition of substances that are naturally (e.g., HSA) or artificially (treatment with carbapenems) induces A. baumannii to enhance expression of resistance determinants and genes regulating competence.

scholarly journals Interplay between meropenem and human serum albumin on expression of carbapenem resistance genes and natural competence in Acinetobacter baumannii

2021 ◽  
Author(s):  
Camila Pimentel ◽  
Casin Le ◽  
Marisel Romina Tuttobene ◽  
Tomas Subils ◽  
Brent Nishimura ◽  
...  
Keyword(s):  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Natural Transformation ◽  
Natural Competence ◽  
Expression Levels ◽  
Carbapenem Resistant ◽  
Synergistic Enhancement

Acinetobacter baumannii A118, a mostly susceptible strain, and AB5075, carbapenem-resistant, were cultured in L-broth or L-broth with different supplements: 3.5% human serum albumin (HSA), human serum (HS), meropenem, or meropenem plus 3.5% HSA. Natural transformation levels were enhanced in A. baumannii A118 and AB5075 cultured in medium supplemented with 3.5 % HSA. Addition of meropenem plus 3.5% HSA caused synergistic enhancement of natural transformation inA. baumannii A118. Medium containing 3.5% HSA or meropenem enhanced the expression levels of the competence and type IV pilus associated genes. The combination meropenem plus 3.5% HSA produced a synergistic augmentation in the expression levels of many of these genes. The addition of HS, which has a high content of HSA, was also an inducer of these genes. Cultures in medium supplemented with HS or 3.5% HSA also affected resistance genes, which were expressed at higher or lower levels depending on the modification required to enhance resistance. The inducing or repressing activity of these modulators also occurred in three more carbapenem-resistant strains tested. An exception was the A. baumanniiAMA16 blaNDM-1 gene, which was repressed in the presence of 3.5% HSA. In conclusion, HSA produces an enhancement of natural transformation and a modification in expression levels of competence genes and antibiotic resistance. Furthermore, when HSA is combined with carbapenems, which may produce stronger cellular stress, the A. baumannii responds increasing the levels of expression of genes involved in natural competence. This process may favor the acquisition of foreign DNA and accelerate evolution.

scholarly journals Involvement of H-NS in Acinetobacter baumannii’s Natural Transformation

2021 ◽  
Author(s):  
Casin Le ◽  
Camila Pimentel ◽  
Marisel Romina Tuttobene ◽  
Tomás Subils ◽  
Jenny Escalante ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Wild Type Strain ◽  
Natural Transformation ◽  
Regulatory Elements ◽  
Wild Type ◽  
Regulation Of Expression ◽  
Expression Levels ◽  
Expression Of Genes ◽  
Foreign Dna

Most Acinetobacter baumannii strains are naturally competent. Although some information is available about factors that enhance or reduce the frequency of transformation of this bacterium, the regulatory elements and mechanisms are barely understood. In this article, we describe studies on the role of H-NS in the regulation of expression of genes related to natural competency and the ability to uptake foreign DNA. The expression levels of the natural transformation-related genes pilA, pilT, pilQ, comEA, comEC, comF, and drpA were significantly increased in a Δhns derivative of Acinetobacter baumannii A118. Complementation of the mutant with a recombinant plasmid harboring hns restored expression levels of six of these genes (pilT remained expressed at high levels) to those of the wild-type strain. The transformation frequency of the A. baumannii A118 Δhns strain was significantly higher than that of the wild-type. Similar, albeit not identical, effects occurred when hns was deleted from the hypervirulent A. baumannii AB5075 strain. Reduction of gene expression in a few cases was not as pronounced as to reach wild-type levels, and expression of comEA was enhanced further. In conclusion, the expression of all seven transformation-related genes was enhanced after deleting hns in A. baumannii A118 and AB5075, and these modifications are accompanied by an increase in the cells’ transformability. The results demonstrate a role of H-NS in A. baumannii’s natural competence.

scholarly journals Involvement of the Histone-Like Nucleoid Structuring Protein (H-NS) in Acinetobacter baumannii’s Natural Transformation

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1083
Author(s):  
Casin Le ◽  
Camila Pimentel ◽  
Marisel R. Tuttobene ◽  
Tomás Subils ◽  
Jenny Escalante ◽  
...  
Keyword(s):  
Wild Type Strain ◽  
Natural Transformation ◽  
Regulatory Elements ◽  
Transformation Frequency ◽  
Wild Type ◽  
Natural Competence ◽  
Expression Levels ◽  
Expression Of Genes ◽  
Foreign Dna

Most Acinetobacter baumannii strains are naturally competent. Although some information is available about factors that enhance or reduce the frequency of the transformation of this bacterium, the regulatory elements and mechanisms are barely understood. In this article, we describe studies on the role of the histone-like nucleoid structuring protein, H-NS, in the regulation of the expression of genes related to natural competency and the ability to uptake foreign DNA. The expression levels of the natural transformation-related genes pilA, pilT, pilQ, comEA, comEC, comF, and drpA significantly increased in a Δhns derivative of A. baumannii A118. The complementation of the mutant with a recombinant plasmid harboring hns restored the expression levels of six of these genes (pilT remained expressed at high levels) to those of the wild-type strain. The transformation frequency of the A. baumannii A118 Δhns strain was significantly higher than that of the wild-type. Similar, albeit not identical, there were consequences when hns was deleted from the hypervirulent A. baumannii AB5075 strain. In the AB5075 complemented strain, the reduction in gene expression in a few cases was not so pronounced that it reached wild-type levels, and the expression of comEA was enhanced further. In conclusion, the expression of all seven transformation-related genes was enhanced after deleting hns in A. baumannii A118 and AB5075, and these modifications were accompanied by an increase in the cells’ transformability. The results highlight a role of H-NS in A. baumannii’s natural competence.

scholarly journals Interaction of Acinetobacter baumannii with Human Serum Albumin: Does the Host Determines the Outcome?

Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 833
Author(s):  
Camila Pimentel ◽  
Casin Le ◽  
Marisel R. Tuttobene ◽  
Tomas Subils ◽  
Krisztina M. Papp-Wallace ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Human Serum Albumin ◽  
Quorum Sensing ◽  
Serum Albumin ◽  
Human Serum ◽  
Acinetobacter Baumannii ◽  
Biofilm Formation ◽  
Model Systems ◽  
Expression Levels ◽  
Multiple Drugs

Acinetobacter baumannii has become a serious threat to human health due to its extreme antibiotic resistance, environmental persistence, and capacity to survive within the host. Two A. baumannii strains, A118 and AB5075, commonly used as model systems, and three carbapenem-resistant strains, which are becoming ever more dangerous due to the multiple drugs they can resist, were exposed to 3.5% human serum albumin (HSA) and human serum (HS) to evaluate their response with respect to antimicrobial resistance, biofilm formation, and quorum sensing, all features responsible for increasing survival and persistence in the environment and human body. Expression levels of antibiotic resistance genes were modified differently when examined in different strains. The cmlA gene was upregulated or downregulated in conditions of exposure to 3.5% HSA or HS depending on the strain. Expression levels of pbp1 and pbp3 tended to be increased by the presence of HSA and HS, but the effect was not seen in all strains. A. baumannii A118 growing in the presence of HS did not experience increased expression of these genes. Aminoglycoside-modifying enzymes were also expressed at higher or lower levels in the presence of HSA or HS. Still, the response was not uniform; in some cases, expression was enhanced, and in other cases, it was tapered. While A. baumannii AB5075 became more susceptible to rifampicin in the presence of 3.5% HSA or HS, strain A118 did not show any changes. Expression of arr2, a gene involved in resistance to rifampicin present in A. baumannii AMA16, was expressed at higher levels when HS was present in the culture medium. HSA and HS reduced biofilm formation and production of N-Acyl Homoserine Lactone, a compound intimately associated with quorum sensing. In conclusion, HSA, the main component of HS, stimulates a variety of adaptative responses in infecting A. baumannii strains.

scholarly journals Accumulation of Antibiotic Resistance Genes in Carbapenem-Resistant Acinetobacter baumannii Isolates Belonging to Lineage 2, Global Clone 1, from Outbreaks in 2012–2013 at a Tehran Burns Hospital

mSphere ◽  
2020 ◽  
Vol 5 (2) ◽  
Author(s):  
Masoumeh Douraghi ◽  
Johanna J. Kenyon ◽  
Parisa Aris ◽  
Mahla Asadian ◽  
Sedighe Ghourchian ◽  
...  
Keyword(s):  
Middle East ◽  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Carbapenem Resistance ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
East Region ◽  
Lineage 2 ◽  
Middle East Region

ABSTRACT The worldwide distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) has become a global concern, particularly in countries where antibiotic prescription is not tightly regulated. However, knowledge of the genomic aspects of CRAB from many parts of the world is still limited. Here, 50 carbapenem-resistant A. baumannii isolates recovered at a single hospital in Tehran, Iran, during several outbreaks in 2012 and 2013 were found to be resistant to multiple antibiotics. They were examined using PCR mapping and multilocus sequence typing (MLST). All Iranian strains belonged to sequence type 328 in the Institut Pasteur MLST scheme (ST328IP), a single-locus variant of ST81IP, and all Iranian strains contained two carbapenem resistance genes, oxa23 and oxa24. The oxa23 gene is in the transposon Tn2006 in AbaR4, which interrupts the chromosomal comM gene. Phylogenetic analysis using whole-genome sequence (WGS) data for 9 isolates showed that they belonged to the same clade, designated the ST81/ST328 clade, within lineage 2 of global clone 1 (GC1). However, there were two groups that included either KL13 or KL18 at the K locus (KL) for capsular polysaccharide synthesis and either a tet39 or an aadB resistance gene, respectively. The genetic context of the resistance genes was determined, and the oxa24 (OXA-72 variant) and tet39 (tetracycline resistance) genes were each in a pdif module in different plasmids. The aadB gene cassette (which encodes gentamicin, kanamycin, and tobramycin resistance) was harbored by pRAY*, and the aphA6 gene (which encodes amikacin resistance) and sul2 gene (which encodes sulfamethoxazole resistance) were each harbored by a different plasmid. The sequences obtained here will underpin future studies of GC1 CRAB strains from the Middle East region. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii strains are among the most critical antibiotic-resistant bacteria causing hospital-acquired infections and treatment failures. The global spread of two clones has been responsible for the bulk of the resistance, in particular, carbapenem resistance. However, there is a substantial gap in our knowledge of which clones and which specific lineages within each clone are circulating in many parts of the world, including Africa and the Middle East region. This is the first genomic analysis of carbapenem-resistant A. baumannii strains from Iran. All the isolates, from a single hospital, belonged to lineage 2 of global clone 1 (GC1) but fell into two groups distinguished by genes in the locus for capsule biosynthesis. The analysis suggests a potential origin of multiply antibiotic-resistant lineage 2 in the Middle East region and highlights the ongoing evolution of carbapenem-resistant GC1 A. baumannii strains. It will enhance future studies on the local and global GC1 population structure.

scholarly journals Novel Aminoglycoside Resistance Transposons and Transposon-Derived Circular Forms Detected in Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

2016 ◽  
Vol 60 (3) ◽  
pp. 1801-1818 ◽  
Author(s):  
Nabil Karah ◽  
Chinmay Kumar Dwibedi ◽  
Karin Sjöström ◽  
Petra Edquist ◽  
Anders Johansson ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Point Mutations ◽  
Antibiotic Resistance Genes ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Aminoglycoside Resistance ◽  
Content Type ◽  
Carbapenem Resistant

Acinetobacter baumanniihas emerged as an important opportunistic pathogen equipped with a growing number of antibiotic resistance genes. Our study investigated the molecular epidemiology and antibiotic resistance features of 28 consecutive carbapenem-resistant clinical isolates ofA. baumanniicollected throughout Sweden in 2012 and 2013. The isolates mainly belonged to clonal complexes (CCs) with an extensive international distribution, such as CC2 (n= 16) and CC25 (n= 7). Resistance to carbapenems was related toblaOXA-23(20 isolates),blaOXA-24/40-like(6 isolates),blaOXA-467(1 isolate), and ISAba1-blaOXA-69(1 isolate). Ceftazidime resistance was associated withblaPER-7in the CC25 isolates. Two classical point mutations were responsible for resistance to quinolones in all the isolates. Isolates with high levels of resistance to aminoglycosides carried the 16S rRNA methylasearmAgene. The isolates also carried a variety of genes encoding aminoglycoside-modifying enzymes. Several novel structures involved in aminoglycoside resistance were identified, including Tn6279, ΔTn6279, Ab-ST3-aadB, and different assemblies of Tn6020and TnaphA6. Importantly, a number of circular forms related to the IS26or ISAba125composite transposons were detected. The frequent occurrence of these circular forms in the populations of several isolates indicates a potential role of these circular forms in the dissemination of antibiotic resistance genes.

scholarly journals Molecular Epidemiology of Emerging bla OXA-23-Like - and bla OXA-24-Like -Carrying Acinetobacter baumannii in Taiwan

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
Shu-Chen Kuo ◽  
Wei-Cheng Huang ◽  
Tzu-Wen Huang ◽  
Hui-Ying Wang ◽  
Jui-Fen Lai ◽  
...  
Keyword(s):  
Molecular Epidemiology ◽  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Aminoglycoside Resistance ◽  
S1 Nuclease ◽  
Content Type ◽  
Class A ◽  
Carbapenem Resistant ◽  
Aminoglycoside Resistance Genes ◽  
Resistance Island

ABSTRACT The rate of recovery of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates has increased significantly in recent decades in Taiwan. This study investigated the molecular epidemiology of CRAB with a focus on the mechanisms of resistance and spread in isolates with bla OXA-23-like or bla OXA-24-like . All 555 CRAB isolates in our multicenter collection, which were recovered from 2002 to 2010, were tested for the presence of class A, B, and D carbapenemase genes. All isolates with bla OXA-23-like or bla OXA-24-like were subjected to pulsed-field gel electrophoresis, and 82 isolates (60 isolates with bla OXA-23-like and 22 isolates with bla OXA-24-like ) were selected for multilocus sequence typing to determine the sequence type (ST) and clonal group (CG) and for detection of additional β-lactamase and aminoglycoside resistance genes. The flanking regions of carbapenem and aminoglycoside resistance genes were identified by PCR mapping and sequencing. The localization of bla OXA was determined by S1 nuclease and I-CeuI assays. The numbers of CRAB isolates carrying bla OXA-23-like or bla OXA-24-like , especially those carrying bla OXA-23-like , increased significantly from 2008 onward. The bla OXA-23-like gene was carried by antibiotic resistance genomic island 1 (AbGRI1)-type structures located on plasmids and/or the chromosome in isolates of different STs (CG92 and novel CG786), whereas bla OXA-24-like was carried on plasmids in CRAB isolates of limited STs (CG92). No class A or B carbapenemase genes were identified. Multiple aminoglycoside resistance genes coexisted in CRAB. Tn 6180 -borne armA was found in 74 (90.2%) CRAB isolates, and 58 (70.7%) isolates had Tn 6179 upstream, constituting AbGRI3. bla TEM was present in 38 (46.3%) of the CRAB isolates tested, with 35 (92.1%) isolates containing bla TEM in AbGRI2-type structures, and 61% of ampC genes had IS Aba1 upstream. We conclude that the dissemination and spread of a few dominant lineages of CRAB containing various resistance island structures occurred in Taiwan.

scholarly journals Frequency of antiseptic resistance genes and reduced susceptibility to biocides in carbapenem-resistant Acinetobacter baumannii

2017 ◽  
Vol 66 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Wen J. Liu ◽  
Li Fu ◽  
Mei Huang ◽  
Jing P. Zhang ◽  
Yang Wu ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Carbapenem Resistant

scholarly journals Evolution of Carbapenem-Resistant Acinetobacter baumannii Revealed through Whole-Genome Sequencing and Comparative Genomic Analysis

2014 ◽  
Vol 59 (2) ◽  
pp. 1168-1176 ◽  
Author(s):  
Henan Li ◽  
Fei Liu ◽  
Yawei Zhang ◽  
Xiaojuan Wang ◽  
Chunjiang Zhao ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Acinetobacter Baumannii ◽  
Genome Sequencing ◽  
Resistance Genes ◽  
Genomic Analysis ◽  
Comparative Genomic Analysis ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Content Type ◽  
Carbapenem Resistant

ABSTRACTAcinetobacter baumanniiis a globally important nosocomial pathogen characterized by an evolving multidrug resistance. A total of 35 representative clinicalA. baumanniistrains isolated from 13 hospitals in nine cities in China from 1999 to 2011, including 32 carbapenem-resistant and 3 carbapenem-susceptibleA. baumanniistrains, were selected for whole-genome sequencing and comparative genomic analysis. Phylogenetic analysis revealed that the earliest strain, strain 1999BJAB11, and two strains isolated in Zhejiang Province in 2004 were the founder strains of carbapenem-resistantA. baumannii. Ten types of AbaR resistance islands were identified, and a previously unreported AbaR island, which comprised a two-component response regulator, resistance-related proteins, and RND efflux system proteins, was identified in two strains isolated in Zhejiang in 2004. Multiple transposons or insertion sequences (ISs) existed in each strain, and these gradually tended to diversify with evolution. Some of these IS elements or transposons were the first to be reported, and most of them were mainly found in strains from two provinces. Genome feature analysis illustrated diversified resistance genes, surface polysaccharides, and a restriction-modification system, even in strains that were phylogenetically and epidemiologically very closely related. IS-mediated deletions were identified in the type VI secretion system region, thecsuEregion, and core lipooligosaccharide (LOS) loci. Recombination occurred in the heme utilization region, and intrinsic resistance genes (blaADCandblaOXA-51-likevariants) and three novelblaOXA-51-likevariants (blaOXA-424,blaOXA-425, andblaOXA-426) were identified. Our results could improve the understanding of the evolutionary processes that contribute to the emergence of carbapenem-resistantA. baumanniistrains and help elucidate the molecular evolutionary mechanism inA. baumannii.

scholarly journals Molecular Epidemiology of Carbapenem-Resistant Acinetobacter baumannii Isolates from Northern Africa and the Middle East

Antibiotics ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 291
Author(s):  
Paul G. Higgins ◽  
Ralf Matthias Hagen ◽  
Bernd Kreikemeyer ◽  
Philipp Warnke ◽  
Andreas Podbielski ◽  
...  
Keyword(s):  
Middle East ◽  
Acinetobacter Baumannii ◽  
Resistance Genes ◽  
Core Genome ◽  
Carbapenem Resistance ◽  
Resistance Mechanisms ◽  
Northern Africa ◽  
Carbapenem Resistant ◽  
Next Generation Sequencing Ngs ◽  
Injured Patients

At the Bundeswehr Hospitals of Hamburg and Westerstede, patients repatriated from subtropical war and crisis zones of Northern Africa and the Middle East were medically treated, including microbiological assessment. Within a six-year interval, 16 Acinetobacter spp. strains, including 14 Acinetobacter baumannii (Ab) isolates with resistance against carbapenems and origins in Afghanistan (n = 4), Iraq (n = 2), Libya (n = 2), and Syria (n = 8) were collected. While clonal relationships of Libyan and Syrian strains had been assessed by superficial next generation sequencing (NGS) and “DiversiLab” repetitive elements sequence-based (rep-)PCR so far, this study provides core genome-based sequence typing and thus more detailed epidemiological information. In detail, sequencing allowed a definitive species identification and comparison with international outbreak-associated Ab strains by core genome multi locus sequence typing (cgMLST) and the identification of MLST lineages, as well as the identification of known resistance genes. The sequence analysis allowed for the confirmation of outbreak-associated clonal clusters among the Syrian and Afghan Ab isolates, indicating likely transmission events. The identified acquired carbapenem resistance genes comprised blaOXA-23, blaOXA-58, blaNDM-1, and blaGES-11, next to other intrinsic and acquired, partly mobile resistance-associated genes. Eleven out of 14 Ab isolates clustered with the previously described international clonal lineages IC1 (4 Afghan strains), IC2 (6 Syrian strains), and IC7 (1 Syrian strain). Identified Pasteur sequence types of the 14 Ab strains comprised ST2 (Syrian), ST25 (Libyan), ST32 (Iraqi), ST81 (Afghan), ST85 (Libyan), and ST1112 (Syrian), respectively. In conclusion, the study revealed a broad spectrum of resistance genes in Ab isolated from war-injured patients from Northern Africa and the Middle East, thereby broadening the scarcely available data on locally abundant clonal lineages and resistance mechanisms.

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