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Fulltext Small, Enigmatic Plasmids of the Nosocomial Pathogen, Acinetobacter baumannii: Good, Bad, Who Knows?

Lean SS, Yeo CC

Front Microbiol, 2017;8:1547.
PMID: 28861061 DOI: 10.3389/fmicb.2017.01547

Acinetobacter baumannii is a Gram-negative nosocomial pathogen that has become a serious healthcare concern within a span of two decades due to its ability to rapidly acquire resistance to all classes of antimicrobial compounds. One of the key features of the A. baumannii genome is an open pan genome with a plethora of plasmids, transposons, integrons, and genomic islands, all of which play important roles in the evolution and success of this clinical pathogen, particularly in the acquisition of multidrug resistance determinants. An interesting genetic feature seen in majority of A. baumannii genomes analyzed is the presence of small plasmids that usually ranged from 2 to 10 kb in size, some of which harbor antibiotic resistance genes and homologs of plasmid mobilization genes. These plasmids are often overlooked when compared to their larger, conjugative counterparts that harbor multiple antibiotic resistance genes and transposable elements. In this mini-review, we will examine our current knowledge of these small A. baumannii plasmids and look into their genetic diversity and phylogenetic relationships. Some of these plasmids, such as the Rep-3 superfamily group and the pRAY-type, which has no recognizable replicase genes, are quite widespread among diverse A. baumannii clinical isolates worldwide, hinting at their usefulness to the lifestyle of this pathogen. Other small plasmids especially those from the Rep-1 superfamily are truly enigmatic, encoding only hypothetical proteins of unknown function, leading to the question of whether these small plasmids are "good" or "bad" to their host A. baumannii.
Fulltext Comparative Genomics of Two ST 195 Carbapenem-Resistant Acinetobacter baumannii with Different Susceptibility to Polymyxin Revealed Underlying Resistance Mechanism

Lean SS, Yeo CC, Suhaili Z, Thong KL

Front Microbiol, 2015;6:1445.
PMID: 26779129 DOI: 10.3389/fmicb.2015.01445

Acinetobacter baumannii is a Gram-negative nosocomial pathogen of importance due to its uncanny ability to acquire resistance to most antimicrobials. These include carbapenems, which are the drugs of choice for treating A. baumannii infections, and polymyxins, the drugs of last resort. Whole genome sequencing was performed on two clinical carbapenem-resistant A. baumannii AC29 and AC30 strains which had an indistinguishable ApaI pulsotype but different susceptibilities to polymyxin. Both genomes consisted of an approximately 3.8 Mbp circular chromosome each and several plasmids. AC29 (susceptible to polymyxin) and AC30 (resistant to polymyxin) belonged to the ST195 lineage and are phylogenetically clustered under the International Clone II (IC-II) group. An AbaR4-type resistance island (RI) interrupted the comM gene in the chromosomes of both strains and contained the bla OXA-23 carbapenemase gene and determinants for tetracycline and streptomycin resistance. AC29 harbored another copy of bla OXA-23 in a large (~74 kb) conjugative plasmid, pAC29b, but this gene was absent in a similar plasmid (pAC30c) found in AC30. A 7 kb Tn1548::armA RI which encodes determinants for aminoglycoside and macrolide resistance, is chromosomally-located in AC29 but found in a 16 kb plasmid in AC30, pAC30b. Analysis of known determinants for polymyxin resistance in AC30 showed mutations in the pmrA gene encoding the response regulator of the two-component pmrAB signal transduction system as well as in the lpxD, lpxC, and lpsB genes that encode enzymes involved in the biosynthesis of lipopolysaccharide (LPS). Experimental evidence indicated that impairment of LPS along with overexpression of pmrAB may have contributed to the development of polymyxin resistance in AC30. Cloning of a novel variant of the bla AmpC gene from AC29 and AC30, and its subsequent expression in E. coli also indicated its likely function as an extended-spectrum cephalosporinase.
Whole-genome analysis of an extensively drug-resistant clinical isolate of Acinetobacter baumannii AC12: insights into the mechanisms of resistance of an ST195 clone from Malaysia

Lean SS, Yeo CC, Suhaili Z, Thong KL

Int J Antimicrob Agents, 2015 Feb;45(2):178-82.
PMID: 25481460 DOI: 10.1016/j.ijantimicag.2014.10.015

Acinetobacter baumannii has emerged as an important nosocomial pathogen owing to its increasing resistance to most, if not all, antibiotics in clinical use. We recently reported the occurrence of extensively drug-resistant (XDR) A. baumannii isolates in a Malaysian tertiary hospital. The genome of one of these XDR isolates (A. baumannii AC12) was completely sequenced and comparative genome analyses were performed to elucidate the genetic basis of its antimicrobial resistance. The A. baumannii AC12 genome consists of a 3.8 Mbp circular chromosome and an 8731 bp cryptic plasmid, pAC12. It belongs to the ST195 lineage and is most closely related to A. baumannii BJAB0715 as well as other strains of the international clone III (IC-III) group. Two antibiotic resistance islands (RIs), designated AC12-RI1 and AC12-RI2, were found in the AC12 chromosome along with a 7 kb Tn1548::armA island conferring resistance to aminoglycosides and macrolides. The 22.8 kb AC12-RI1 interrupts the comM gene and harbours the carbapenem resistance gene blaOXA-23 flanked by ISAba1 within a Tn2006-like structure. AC12-RI1 also harbours resistance determinants for aminoglycosides, tetracyclines and sulphonamides. The 10.3 kb IS26-flanked AC12-RI2 is a derivative of AbGRI2-1, containing aphA1b and blaTEM genes (conferring aminoglycoside and β-lactam resistance, respectively). The presence of numerous genes mediating resistance to various antibiotics in novel RI structures as well as other genes encoding drug transporters and efflux pumps in A. baumannii AC12 most likely contributed to its XDR characteristics.
The state of ESKAPE in Malaysia

McNeil HC, Lean SS, Lim V, Clarke SC

Int J Antimicrob Agents, 2016 Nov;48(5):578-579.
PMID: 27742200 DOI: 10.1016/j.ijantimicag.2016.08.011
Fulltext Draft Genome Sequence of Methicillin-Resistant Staphylococcus aureus KT/Y21, a Sequence Type 772 (ST772) Strain Isolated from a Pediatric Blood Sample in Terengganu, Malaysia

Suhaili Z, Lean SS, Yahya A, Mohd Desa MN, Ali AM, Yeo CC

Genome Announc, 2014;2(2).
PMID: 24723714 DOI: 10.1128/genomeA.00271-14

Here, we report the draft genome sequence of a methicillin-resistant Staphylococcus aureus (MRSA) strain, KT/Y21, isolated from a blood sample of a pediatric patient. This strain belongs to sequence type 772 (ST772), harbors the staphylococcal cassette chromosome mec element (SCCmec) type V, and is positive for the Panton-Valentine leukocidin (PVL) pathogenic determinant.
Fulltext Endemicity of Acinetobacter calcoaceticus-baumannii Complex in an Intensive Care Unit in Malaysia

Dhanoa A, Rajasekaram G, Lean SS, Cheong YM, Thong KL

J Pathog, 2015;2015:789265.
PMID: 26819759 DOI: 10.1155/2015/789265

Introduction. Acinetobacter calcoaceticus-baumannii complex (ACB complex) is a leading opportunistic pathogen in intensive care units (ICUs). Effective control of spread requires understanding of its epidemiological relatedness. This study aims to determine the genetic relatedness and antibiotic susceptibilities of ACB complex in an ICU in Malaysia. Methodology. Pulsed field gel electrophoresis (PFGE), E-test, and disk diffusion were used for isolates characterization. Results. During the study period (December 2011 to June 2012), 1023 patients were admitted to the ICU and 44 ACB complex (blood, n = 21, and blind bronchial aspirates, n = 23) were recovered from 38 ICU patients. Six isolates were from non-ICU patients. Of the 44 ICU isolates, 88.6% exhibited multidrug-resistant (MDR) patterns. There was high degree of resistance, with minimum inhibitory concentration90 (MIC90) of >32 μg/mL for carbapenems and ≥256 μg/mL for amikacin, ampicillin/sulbactam, and cefoperazone/sulbactam. Isolates from the main PFGE cluster were highly resistant. There was evidence of dissemination in non-ICU wards. Conclusion. High number of clonally related MDR ACB complex was found. While the ICU is a likely reservoir facilitating transmission, importation from other wards may be important contributor. Early identification of strain relatedness and implementation of infection control measures are necessary to prevent further spread.
Fulltext Genome sequence of Acinetobacter baumannii AC12, a polymyxin-resistant strain isolated from Terengganu, Malaysia

Gan HM, Lean SS, Suhaili Z, Thong KL, Yeo CC

J Bacteriol, 2012 Nov;194(21):5979-80.
PMID: 23045494 DOI: 10.1128/JB.01466-12

Acinetobacter baumannii is a major cause of nosocomial infection worldwide. We report the draft genome sequence of A. baumannii AC12, a multidrug-resistant nosocomial strain with additional resistance to carbapenems and polymyxin. The genome data will provide insights into the genetic basis of antimicrobial resistance and its adaptive mechanism.
Fulltext Draft genome sequence of Staphylococcus aureus KT/312045, an ST1-MSSA PVL positive isolated from pus sample in East Coast Malaysia

Suhaili Z, Lean SS, Mohamad NM, Rachman AR, Desa MN, Yeo CC

Genom Data, 2016 Sep;9:111-2.
PMID: 27508119 DOI: 10.1016/j.gdata.2016.07.002

Most of the efforts in elucidating the molecular relatedness and epidemiology of Staphylococcus aureus in Malaysia have been largely focused on methicillin-resistant S. aureus (MRSA). Therefore, here we report the draft genome sequence of the methicillin-susceptible Staphylococcus aureus (MSSA) with sequence type 1 (ST1), spa type t127 with Panton-Valentine Leukocidin (pvl) pathogenic determinant isolated from pus sample designated as KT/314250 strain. The size of the draft genome is 2.86 Mbp with 32.7% of G + C content consisting 2673 coding sequences. The draft genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number AOCP00000000.
Fulltext Prevalence and Genetic Characterization of Carbapenem- and Polymyxin-Resistant Acinetobacter baumannii Isolated from a Tertiary Hospital in Terengganu, Malaysia

Lean SS, Suhaili Z, Ismail S, Rahman NI, Othman N, Abdullah FH, et al.

ISRN Microbiol, 2014;2014:953417.
PMID: 25006521 DOI: 10.1155/2014/953417

Nosocomial infection caused by Acinetobacter baumannii is of great concern due to its increasing resistance to most antimicrobials. In this study, 54 nonrepeat isolates of A. baumannii from the main tertiary hospital in Terengganu, Malaysia, were analyzed for their antibiograms and genotypes. Out of the 54 isolates, 39 (72.2%) were multidrug resistant (MDR) and resistant to carbapenems whereas 14 (25.9%) were categorized as extensive drug resistant (XDR) with additional resistance to polymyxin B, the drug of "last resort." Pulsed-field gel electrophoresis analyses showed that the polymyxin-resistant isolates were genetically diverse while the carbapenem-resistant isolates were clonally related. The 14 XDR isolates were further investigated for mutations in genes known to mediate polymyxin resistance, namely, pmrCAB, and the lipopolysaccharide biosynthesis genes, lpxA, lpxC, lpxD, and lpsB. All 14 isolates had a P102H mutation in pmrA with no mutation detected in pmrC and pmrB. No mutation was detected in lpxA but each polymyxin-resistant isolate had 2-4 amino acid substitutions in lpxD and 1-2 substitutions in lpxC. Eight resistant isolates also displayed a unique H181Y mutation in lpsB. The extent of polymyxin resistance is of concern and the novel mutations discovered here warrant further investigations.
Fulltext Comparative genomic analysis of clinical Acinetobacter nosocomialis isolates from Terengganu, Malaysia led to the discovery of a novel tetracycline-resistant plasmid

Mohd Rani F, Lean SS, A Rahman NI, Ismail S, Alattraqchi AG, Amonov M, et al.

J Glob Antimicrob Resist, 2022 Dec;31:104-109.
PMID: 36049733 DOI: 10.1016/j.jgar.2022.08.019

OBJECTIVES: To analyse the genome sequences of four archival Acinetobacter nosocomialis clinical isolates (designated AC13, AC15, AC21 and AC25) obtained from Terengganu, Malaysia in 2011 to determine their genetic relatedness and basis of antimicrobial resistance.
METHODS: Antimicrobial susceptibility profiles of the A. nosocomialis isolates were determined by disk diffusion. Genome sequencing was performed using the Illumina NextSeq platform.
RESULTS: The four A. nosocomialis isolates were cefotaxime resistant whereas three isolates (namely, AC13, AC15 and AC25) were tetracycline resistant. The carriage of the blaADC-255-encoded cephalosporinase gene is likely responsible for cefotaxime resistance in all four isolates. Phylogenetic analysis indicated that the three tetracycline-resistant isolates were closely related, with an average nucleotide identity of 99.9%, suggestive of nosocomial spread, whereas AC21 had an average nucleotide identity of 97.9% when compared to these three isolates. The tetracycline-resistant isolates harboured two plasmids: a 13476 bp Rep3-family plasmid of the GR17 group designated pAC13-1, which encodes the tetA(39) tetracycline-resistance gene, and pAC13-2, a 4872 bp cryptic PriCT-1-family plasmid of a new Acinetobacter plasmid group, GR60. The tetA(39) gene was in a 2 001 bp fragment flanked by XerC/XerD recombination sites characteristic of a mobile pdif module. Both plasmids also harboured mobilisation/transfer-related genes.
CONCLUSIONS: Genome sequencing of A. nosocomialis isolates led to the discovery of two novel plasmids, one of which encodes the tetA(39) tetracycline-resistant gene in a mobile pdif module. The high degree of genetic relatedness among the three tetracycline-resistant A. nosocomialis isolates is indicative of nosocomial transmission.