The complete genome, comparative and functional analysis of Stenotrophomonas maltophiliareveals an organism heavily shielded by drug resistance determinants
- Lisa C Crossman1,
- Virginia C Gould2,
- J Maxwell Dow3,
- Georgios S Vernikos1,
- Aki Okazaki2,
- Mohammed Sebaihia1,
- David Saunders1,
- Claire Arrowsmith1,
- Tim Carver1,
- Nicholas Peters1,
- Ellen Adlem1,
- Arnaud Kerhornou1,
- Angela Lord1,
- Lee Murphy1,
- Katharine Seeger1,
- Robert Squares1,
- Simon Rutter1,
- Michael A Quail1,
- Mari-Adele Rajandream1,
- David Harris1,
- Carol Churcher1,
- Stephen D Bentley1,
- Julian Parkhill1Email author,
- Nicholas R Thomson1 and
- Matthew B Avison2Email author
© Crossman et al.; licensee BioMed Central Ltd. 2008
Received: 14 January 2008
Accepted: 17 April 2008
Published: 17 April 2008
Stenotrophomonas maltophilia is a nosocomial opportunistic pathogen of the Xanthomonadaceae. The organism has been isolated from both clinical and soil environments in addition to the sputum of cystic fibrosis patients and the immunocompromised. Whilst relatively distant phylogenetically, the closest sequenced relatives of S. maltophilia are the plant pathogenic xanthomonads.
The genome of the bacteremia-associated isolate S. maltophilia K279a is 4,851,126 bp and of high G+C content. The sequence reveals an organism with a remarkable capacity for drug and heavy metal resistance. In addition to a number of genes conferring resistance to antimicrobial drugs of different classes via alternative mechanisms, nine resistance-nodulation-division (RND)-type putative antimicrobial efflux systems are present. Functional genomic analysis confirms a role in drug resistance for several of the novel RND efflux pumps. S. maltophilia possesses potentially mobile regions of DNA and encodes a number of pili and fimbriae likely to be involved in adhesion and biofilm formation that may also contribute to increased antimicrobial drug resistance.
The panoply of antimicrobial drug resistance genes and mobile genetic elements found suggests that the organism can act as a reservoir of antimicrobial drug resistance determinants in a clinical environment, which is an issue of considerable concern.
The rise of antimicrobial drug resistance in bacteria is one of the biggest threats to healthcare provision in the developed world. Few new antimicrobial drugs are undergoing clinical trials, and almost none are effective against Gram-negative multi-drug resistant (MDR) pathogens . A return to the pre-antibiotic era is a possibility, and for some infections is the current reality .
Antimicrobial resistance in historically common pathogens is usually either acquired on a mobile genetic element or results from a mutation . However, some opportunistic pathogens are intrinsically resistant to the actions of a number of antimicrobial classes. These tend to be of environmental origin, and their intrinsic drug resistance determinants either provide resistance to antibiotics produced by competitors, or represent broad-spectrum methods for removing toxic compounds or waste products that, by chance, protect against antimicrobials [3, 4]. It is known that established opportunistic infections are very difficult to treat due to the MDR nature of the causative bacteria .
The most common intrinsically MDR opportunistic pathogens are the non-fermenting Gram-negative bacilli typified by Pseudomonas aeruginosa. In this case, intrinsic resistance is due to a battery of efflux pumps, specific antibiotic hydrolyzing enzymes, and intrinsically low outer membrane permeability. When intrinsically MDR bacteria then acquire resistance to those few drugs that can kill them, the result is an isolate resistant to all clinically available antimicrobials. This pan-resistant phenotype is observed in P. aeruginosa isolates with increasing frequency .
S. maltophilia is the third most common nosocomial non-fermenting Gram-negative bacilli . A recent study of intensive care patients in the USA found that 4.3% of almost 75,000 Gram-negative infections studied were caused by S. maltophilia . Isolates are intrinsically resistant to β-lactams, aminoglycosides, macrolides, and many older quinolones .
S. maltophilia is found in soil and water, and routinely resides in showerheads and other moist places where it grows as biofilm. It is a truly opportunistic pathogen, and patient to patient spread has not been reported, though small outbreaks have been seen due to contaminated water sources . Consistent with this, we find that isolates are generally genotypically and phenotypically diverse [10–12]. However, there is phylogenetic clustering, with about half of clinical isolates being very similar to each other, even across a wide geographical range. Members of this group, termed phylogenetic group A, may be better at causing infections than other S. maltophilia isolates . The two most common diseases caused by S. maltophilia are bacteremia and pneumonia with infection being via an indwelling catheter or ventilator, respectively . Respiratory tract colonization is seen in about a third of all cystic fibrosis (CF) patients; nevertheless, there is controversy as to whether this leads to a poorer clinical outcome or morbidity [14, 15].
Bioinformatic and functional genomic analyses on the complete genome sequence emphasize factors with proven or potential contribution to antibiotic resistance, persistence and virulence. The findings reveal the remarkable capacity of S. maltophilia for multidrug resistance and environmental adaptability that underpins its importance as an emerging opportunistic nosocomial pathogen.
Results and discussion
Total genome overview
The sequenced isolate is from a typical presentation: an elderly male patient undergoing chemotherapy at the Bristol Oncology Unit, Bristol, UK in 1998 developed a bloodstream infection that did not respond to therapy with piperacillin/tazobactam, ceftazidime or imipenem. S. maltophilia K279a was cultured from a blood sample taken shortly before death . K279a falls into phylogenetic group A, and has typical antimicrobial resistance properties [13, 17, 18]. Accordingly, it was thought suitable as a representative genome sequence strain.
In Gram-negative nosocomial pathogens, MDR is usually mediated by the over-production of resistance-nodulation-division (RND) type efflux pumps. These pumps tend to have broad substrate profiles, including organic solvents, disinfectants and antimicrobial drugs from a number of different classes. Cytoplasmic efflux is driven by dissipation of the proton-motive force across the inner membrane. Two additional components are needed to remove substrates from the cell, forming a tripartite efflux pump complex that spans the envelope. A particular periplasm-spanning membrane-fusion protein (MFP) is usually specific to each RND efflux protein, and it is common to find the pair encoded as part of an operon. A third component, the outer membrane protein (OMP), can be encoded in the same operon, but there tend to be fewer different OMPs than RND/MFP pairs in a cell, meaning that the OMPs are often promiscuous .
The K279a sequence carries nine RND-type efflux pump genes that fall into the drug resistance type based on sequence homology. Homologues of two known S. maltophilia tripartite efflux pump operons are present, smeABC (Smlt4474-6) and smeDEF (Smlt4070-2), representing MFP, RND and OMP genes, respectively, in each case. SmeABC was first characterized in the clinical S. maltophilia isolate ULA511 , which is phylogenetically closely related to K279a . Disruption of smeAB in ULA-511, or in a hyper-resistant mutant background, had no effect on drug resistance. However, disruption of smeC reduced the minimum inhibitory concentration (MIC) of a variety of antimicrobials against ULA-511, so SmeC may act as an OMP in at least one functional tripartite antimicrobial efflux pump .
Characteristics of Sme efflux transporters in S. maltophilia K279a
Known or putative regulation mechanism
Closest match to a known antimicrobial efflux protein
Two component regulator (SmeSR, Smlt4477-8)
S. maltophilia SmeABC 
Tet-R type (SmeT, Smlt4073)
S. maltophilia SmeDEF [17,22]
LysR type (Smlt1827)
51%, 56% and 48% amino acid identity, respectively, to P. aeruginosa MexEF-OprN 
Two component regulator (Smlt2199-30)
44% and 59% amino acid identity, respectively, to AdeAB of A. baumanii 
TetR type (Smlt3169)
39% and 49% amino acid identity, respectively, to AcrAB of M. morganii 
<30% identity to other known antimicrobial efflux proteins
TetR type (Smlt3926)
<30% identity to other known antimicrobial efflux proteins
41%, 50% and 44% amino acid identity, respectively, to MtdABC of E. coli 
MICs of a variety of antimicrobials against S. maltophilia K279a and derivatives lacking specific functional RND efflux pump genes
Putative and known antimicrobial drug and heavy metal resistance genes in the S. maltophilia K279a genome sequence
Putative gene product
Putative aminoglycoside phosphotransferase
Putative aminoglycoside 2' N-acetyltransferase
Known aminoglycoside 3' phosphotransferase
Putative streptomycin 3" phosphotransferase/kinase
Known aminoglycoside 6'N acetyltransferase
Putative spectinomycin phosphotransferase
Putative chloramphenicol acetyltransferase
Putative quinolone resistance protein
Putative MFS-type tripartite efflux transporter
Putative ABC-type tripartite efflux transporter
Putative ABC efflux transporter and MFP
Putative MFS-type tripartite efflux transporter
Putative RND-type tripartite efflux transporter
Putative RND-type efflux protein and MFP
Multidrug/fusaric acid resistance protein
Putative RND-type efflux protein and MFP
Putative RND-type efflux protein and MFP
Putative RND-type efflux protein and MFP
Known RND-type tripartite efflux protein
Putative RND-type tripartite efflux proteins and MFP
Known RND-type tripartite efflux protein
Known Beta-lactamase - L1
Known Beta-lactamase - L2
Putative kasuagamycin resistance protein
Organic solvent tolerance protein
copLABMGCDF Smlt2445/Smlt2443 copL2A2B2 copCD
Genes encoding six other putative RND family tripartite efflux pumps are found in the K279a genome sequence. However, these are more closely related to cation/metal efflux pumps than to antimicrobial RND efflux pumps, and are designated SmmABC to TUV. K279a additionally encodes several alternative heavy metal resistance mechanisms that are associated with a complex mobile region of DNA. These include arsenic, mercury, and copper resistance. Alternative copper resistance genes are specified elsewhere in the genome. Heavy metal resistance (to cadmium via an efflux protein) has been described in S. maltophilia D457R .
Potential mobile regions and their major characteristics
Putative length, approx. (bp)
G+C content (%)
Putatively bounded by (repeat length, bp)
Potential conjugative transposon
Hypotheticals, lipoproteins and an efflux protein cargo
Potential complex transposon insertion
Efflux transporters, mercury, arsenic and copper resistance, co-integrate resolution and integrases. May be a multiple insertion*
Potential complex transposon insertion
Tra genes and adhesins, DNA repair, conserved and unique hypotheticals. May be a multiple insertion. Carries IS elements and Tn5044 similarity
Seven intact copies and two pseudogenic copies
Eleven intact copies
Four intact copies
Phage cluster 1
Putative pseudogenic phage. Putative IS insertion and tRNA located centrally
Phage cluster 2
Putative intact phage
There is no evidence in K279a for a class one integron specifying sulfonamide resistance as has recently been seen in a number of S. maltophilia isolates , and K279a is sensitive to trimethoprim-sulphamethoxazole.
S. maltophilia harbor giant phage ; although potential prophages were identified in K279a, there is no evidence for giant lysogenic phage.
Secretion systems and extracellular enzymes
Type I, II (sec), IV and V (autotransporter) as well as the twin arginine secretion systems genes are present in the K279a genome sequence. Surprisingly, there are no type III secretion genes in K279a. Type III secretion components are related to the flagella apparatus . The flagella apparatus of S. maltophilia is highly conserved with the X. campestris system and there is no evidence to suggest that these components could function in type III secretion. Secreted extracellular enzyme genes were found in the genome. K279a encodes non-hemolytic phospholipase C (plcN1, Smlt1755) as well as enzymes from the phospholipase D family. Phospholipase cleaves phospholipids to fatty acids and is implicated in virulence due to its ability to degrade cell membranes. There is evidence that phospholipases contribute towards virulence in Burkholderia pseudomallei . Other extracellular enzymes, including DNase, gelatinase, hemolysin, lipases, proteinase K and proteases, have been characterized and implicated in disease in S. maltophilia . The major extracellular protease of K279a, StmPr1 (Smlt0861), has also been implicated as a virulence determinant .
Pili, fimbriae and adhesins
S. maltophilia produces various pili/fimbriae that are implicated in adhesion and biofilm formation . This type of aggregative behavior is likely to be associated with colonization of biotic and abiotic surfaces, evasion of the host immune response as well as increased drug resistance.
The Smf-1 fimbrial operon includes Smlt0706-Smlt0709. These 17 kDa subunit fimbriae mediate adherence, participate at early stages of biofilm formation  and can agglutinate red blood cells. Smf-1, seen as peritrichous semi-flexible fimbriae of 5-7 nm under electron microscopy, are produced at 37°C but not 18°C. Two distinct loci, Smlt1508-12 and Smlt0732-6, comprise further sets of putative pili/fimbrial genes that include fimbrial subunit and chaperone/usher proteins.
A TadE-like pili/fimbrial gene cluster is located at Smlt2867-Smlt2875. In Actinobacillus, bundled Flp pili are required for tight adherence and strongly attached biofilm on solid surfaces in vitro, which is likely to be required in oral cavity colonization and initiation of periodontal disease .
Type IV pili are implicated in adherence and autoaggregation in enteropathogenic E. coli. In some species they have been associated with twitching motility and biofilm formation (for example, the obligate plant pathogen Xylella fastidiosa and P. aeruginosa). Subunits and associated apparatus specifying the type IV pilus are scattered throughout the genome of K279a. K279a also carries a gene cluster that shares significant similarity with a locus specifying the giant cable pilus of Burkholderia cenocepacia. This pilus has been implicated in the pathogenicity of B. cenocepacia in CF patients . However, not all pathogenic CF isolates of B. cenocepacia carry cbl genes; this can also be the case in other Burkholderia spp. . Alternative potential adhesins are encoded in the genome, including an afimbrial adhesin and Hep-hag family adhesins.
In this bacteremia-associated isolate, K279a, there are three members of the YadA family of BuHA proteins that contain numerous Hep-Hag repeat domains . Two hemagglutinin/hemolysin family proteins are present as pseudogenes. Hemolysin activator Smlt1389, and outer membrane surface filamentous heamagglutinin (FHA) Smlt1390 and Smlt4452 are present. Filamentous heamagglutinin is an important virulence factor in Bordetella pertussis, being involved in related adhesion and spread of bacteria through the respiratory tract .
Intercellular and intracellular signaling
Quorum sensing (cell-cell signaling) is important in infection models of P. aeruginosa, and quorum-sensing signals that coordinate biofilm formation have been identified in CF sputum along with biofilm-like structures . S. maltophilia also carries out cell-cell signaling; however, the S. maltophilia system does not employ the usual LuxIR regulators [43, 44]. Instead, S. maltophilia uses the Xanthomonas and Xylella signaling system mediated by a diffusible signal molecule, DSF [45, 46]. DSF activity has been detected in a number of strains of S. maltophilia, including K279a, and controls resistance to several antibiotics, aggregative and biofilm behavior and virulence in a nematode model . The K279a proteome contains no n-acyl homoserine lactone (N-AHL) synthases of either the LuxI or LuxM type and no LuxS protein (implicated in autoinducer 2 synthesis in a wide range of bacteria). K279a does encode a single LuxR type regulator with an N-AHL autoinducer-binding domain. Such orphan LuxR-like proteins have been described in Xanthomonas oryzae pv oryzae (X. oryzae)  and X. campestris , which do not synthesize N-AHLs. These proteins may interact with a plant host component rather than bind N-AHLs.
DSF perception in X. campestris is linked to altered levels of the second messenger cyclic di-GMP through the action of the HD-GYP phosphodiesterase domain regulator RpfG . Cyclic-di-GMP regulates a range of functions, including developmental transitions, adhesion, biofilm formation and virulence in diverse bacteria . Cyclic-di-GMP levels are influenced by synthesis and degradation acted on by the protein domains GGDEF, EAL and HD-GYP. K279a encodes 33 proteins with a potential role in cyclic di-GMP turnover: 3 proteins with an EAL domain; 18 with a single GGDEF domain; 10 with GGDEF and EAL domains; and two HD-GYP domain proteins, including RpfG. Most of these proteins contain additional signal input domains, suggesting that their activities (and therefore cyclic di-GMP levels) are responsive to diverse environmental cues.
Polysaccharides are integral components of the extracellular matrix of bacterial biofilms and may play a role in resistance of bacteria to antibiotics. In xanthomonads, the gum gene cluster specifies production of the exopolysaccharide xanthan that is important in biofilm formation as well as being a commercially important product. X. fastidiosa produces fastidian gum, a truncated xanthan that is encoded by a reduced gum gene cluster . There are no gum gene cluster orthologues in K279a; hence, this strain does not produce either xanthan or a modified version. Additionally, K279a does not carry genes for cellulose production, nor the exopolysaccharide cepacian, produced by some strains of B. cenocepacia.
Gene products implicated in the formation of intermediates of lipopolysaccharides and exopolysaccharides have been identified in K279a. XanAB are involved in UDP-glucose and GDP-mannose biosynthesis whilst RmlAC are involved in the synthesis and interconversion of TDP-sugars. XanB shares significant homology with phosphomannose isomerase, a key enzyme in the biosynthesis of P. aeruginosa alginate. Alginate is a key polysaccharide and is upregulated in CF sputum isolates from patients that have been infected with P. aeruginosa over a considerable length of time. Mutations in xanB and rmlAC affect biofilm formation and twitching motility in S. maltophilia WR-C . The xanA gene, also known as spgM, is a phosphoglucomutase that shares similarity with P. aeruginosa algC . K279a also specifies an orthologue of alginate lyase (Smlt1473), which is intriguing, since in CF lungs, the organisms are likely to be in contact with alginate-producing P. aeruginosa.
Comparing the genomes of S. maltophilia and X. campestris- two sides of the same coin?
The genome sequence of the bacteremia-associated S. maltophilia isolate K279a carries a startling array of antimicrobial drug resistance gene determinants. Knockout mutagenesis confirms the involvement of a number of novel RND efflux genes in resistance to a variety of different classes of antimicrobials.
The current drug of choice for treating S. maltophilia infections is trimethoprim-sulphamethoxazole, but resistance is seen in S. maltophilia isolates due to a mobile determinant [29, 60]. Other drugs with reasonable activity against S. maltophilia are minocycline and newer fluoroquinolones . However, mutants resistant to these last resort drugs are readily selected in vitro. One mutation may be sufficient to cause resistance to these drugs, and worryingly, this mutation can be selected for in the presence of a front-line antimicrobial such as amikacin .
The panoply of antimicrobial drug resistance genes and mobile genetic elements is an issue of clinical concern. S. maltophilia can also provide antibiotic resistance protection for sensitive P. aeruginosa and Serratia marcescens strains growing nearby . Even more importantly, the organism potentially acts as a reservoir of antibiotic resistance determinants in medically relevant environments.
K279a possesses an unusual cell density-signaling pathway like that of its plant pathogenic xanthomonad relatives. K279a does produce extracellular enzymes such as protease StmPr1 and phospholipases; however, previous studies on clinical isolates have reported the production of other extracellular enzymes by S. maltophilia, suggesting that such virulence factors may be strain-specific. Comparison of K279a with X. campestris illustrates the movements of mobile genetic elements, the acquisition of potentially human pathogenic factors such as hemagglutinin, hemolysins and the loss of plant pathogenic factors such as the extracellular enzyme polygalacturonate lyase.
In conclusion, the S. maltophilia genome sequence reveals the capacity of this organism for environmental adaptations that presumably contribute to its persistence in vivo. As expected of a true opportunistic pathogen, the S. maltophilia genome does not suggest a highly virulent organism. However, the large number of pili/fimbrial genes does indicate a strong ability to attach to catheters and ventilators, from which infections of the blood or lungs arise. With its MDR phenotype and ability to attach, it is clear why this organism is persistent and difficult to eradicate. We are starting to build up a picture of an organism that is a true opportunist, which, while lacking many conventional key virulence determinants, has nevertheless emerged as a considerable threat.
Materials and methods
Sequencing strategy and annotation
S. maltophilia K279a was grown on Nutrient broth (Oxoid Cambridge, Cambridgeshire, UK) and genomic DNA was isolated using cetyltrimethylammonium bromide.
DNA was sonicated, size selected, and libraries were constructed in pUC19, pMAQ1b and pBACe3.6. The genome assembly was based on 3,381, 41,541 and 21,977 paired end-reads, respectively, from pUC19 libraries (of insert sizes 1.4-2.0 kb, 2.0-2.8 kb and 3.0-3.3 kb) and from 6,890, 314 and 69 paired end-reads, respectively, from pMAQ1b libraries (of insert sizes 5.5-6.0 kb, 9-10 kb and 10-12 kb), to give a 10.76-fold sequence coverage of the genome. We generated 1,250 and 106 reads, respectively, to produce a scaffold from 15-18 and 20-25 kb libraries in pBACe3.6. The genome was sequenced, finished and annotated as previously described . To ensure that all bases were covered by reads on both strands or with different sequencing chemistries, and to fill gaps, 789 extra reads were generated. Repeats were bridged using read-pairs or end-sequenced PCR products. The total shotgun size was 53,580,262 Mb with a total genome coverage of 11.05-fold. Orthologous genes were determined by reciprocal best match analysis.
Disruption of putative efflux pump genes and MIC determination
Genes were disrupted using a modified method of that previously described . Genes were amplified by PCR in two non-overlapping fragments, with HindIII being introduced such that the two fragments could be ligated together, resulting in a mutant gene having a large deletion and a frameshift mutation. The primers used are listed in Additional data file 2. Mutated genes were used to replace wild-type sequences on the chromosome of K279a using the gene replacement approach described previously. Agar dilution MICs of antimicrobials against K279a and its derivatives were determined according to British Society for Antimicrobial Chemotherapy (BSAC)-approved methods .
Additional data files
The following additional data are available with the online version of this paper. Additional data file 1 shows the shared genes between K279a and X. campestris, and the genes unique to K279a determined by reciprocal best match analysis. Additional data file 2 is a table listing the primer sequences used in the generation of gene knock-outs.
Artemis Comparison Tool
British Society for Antimicrobial Chemotherapy
membrane fusion protein
minimum inhibitory concentration
n-acyl homoserine lactone
outer membrane protein
The authors thank the core informatics and sequencing departments at the Wellcome Trust Sanger Institute. This work was supported by the Wellcome Trust and the BSAC.
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