Small Klebsiella pneumoniae Plasmids: Neglected Contributors to Antibiotic Resistance

Abstract

Klebsiella pneumoniae is the causative agent of community- and, more commonly, hospital-acquired infections. Infections caused by this bacterium have recently become more dangerous due to the acquisition of multiresistance to antibiotics and the rise of hypervirulent variants. Plasmids usually carry genes coding for resistance to antibiotics or virulence factors, and the recent sequence of complete K. pneumoniae genomes showed that most strains harbor many of them. Unlike large plasmids, small, usually high copy number plasmids, did not attract much attention. However, these plasmids may include genes coding for specialized functions, such as antibiotic resistance, that can be expressed at high levels due to gene dosage effect. These genes may be part of mobile elements that not only facilitate their dissemination but also participate in plasmid evolution. Furthermore, high copy number plasmids may also play a role in evolution by allowing coexistence of mutated and non-mutated versions of a gene, which helps to circumvent the constraints imposed by trade-offs after certain genes mutate. Most K. pneumoniae plasmids 25-kb or smaller replicate by the ColE1-type mechanism and many of them are mobilizable. The transposon Tn1331 and derivatives were found in a high percentage of these plasmids. Another transposon that was found in representatives of this group is the bla_KPC-containing Tn4401. Common resistance determinants found in these plasmids were aac(6′)-Ib and genes coding for β-lactamases including carbapenemases.

Introduction

Klebsiella pneumoniae, although usually carried by healthy humans, is also the causative agent of community- and, more commonly, hospital-acquired infections, accounting for more than 30% of those caused by Gram-negative bacteria (Kalpoe et al., 2012; Shon et al., 2013; Li et al., 2014; Calfee, 2017; Navon-Venezia et al., 2017). K. pneumoniae became more dangerous in recent years due to the acquisition of multidrug resistance (Almaghrabi et al., 2014; Chen et al., 2014a; Ramirez et al., 2016; Rojas et al., 2017b) and the emergence of hypervirulent variants (Decre et al., 2011; Kalpoe et al., 2012; Shon et al., 2013). The most common diseases in Western countries, caused by classic (non-hypervirulent) strains, are urinary tract infections, pneumonia, septicemias, meningitis, and soft tissue infections (Shon et al., 2013; Ramirez et al., 2016; Calfee, 2017; Martel et al., 2017; Gupta et al., 2018; Osman et al., 2018). K. pneumoniae may also play a role in ankylosing spondylitis and Crohn’s disease (Rashid et al., 2013, 2016). Hypervirulent variants overproduce capsular polysaccharide and are hypermucoviscous, a phenotype defined when an inoculation loop or needle generates a viscous string >5 mm in length by stretching bacterial colonies on an agar plate (Shon et al., 2013). They are characterized for showing metastatic spread and causing life-threatening community-acquired infections like liver abscess, pneumonia, osteomyelitis, meningitis as well as endophthalmitis in immunocompetent healthy individuals (Cheng et al., 1991; Chen et al., 2004, 2019; Sobirk et al., 2010; Decre et al., 2011; Shon et al., 2013; Prokesch et al., 2016; Martel et al., 2017; Zhan et al., 2017; Gupta et al., 2018; Jun, 2018; Osman et al., 2018; Yao et al., 2018; Marr and Russo, 2019).

As it is the case with most bacteria, virulence factors and drug resistance traits are commonly encoded by K. pneumoniae plasmids (Nassif and Sansonetti, 1986; Nassif et al., 1989a, b; Wacharotayankun et al., 1993; Deleo et al., 2014; Ramirez et al., 2014a; Navon-Venezia et al., 2017; Peirano et al., 2017; Rozwandowicz et al., 2018; Turton et al., 2018). The recent completion and analysis of genomes of numerous K. pneumoniae strains clarified different characteristics of their chromosomes and showed that they usually harbor several plasmids with a broad range of sizes from a few to several hundred kb (Nassif et al., 1989a; Liu et al., 2012; Ramirez et al., 2012, 2014b, 2016; Deleo et al., 2014; Martin and Bachman, 2018). The larger plasmids are usually low copy number and may include genes and functions like antibiotic resistance, virulence factors, and conjugation properties. This rich combination of genes involved in virulence and resistance to treatment, together with the ability to disseminate these traits, attracted the majority of the efforts to study the properties and biology of K. pneumoniae plasmids (Chen et al., 2004; Soler Bistue et al., 2008; Garcia-Fernandez et al., 2012; Mathers et al., 2015; Conlan et al., 2016; Rojas et al., 2017a, b; Zhou et al., 2017; Desmet et al., 2018). However, although carrying a more modest number of genes, small high-copy number plasmids are of interest because they have a significant impact on bacterial infection harboring a variety of resistance genes that are expressed at high levels and that are usually included in mobile elements. These plasmids also play important, albeit still understudied, roles in plasmid evolution through events mediated by mobile elements as well as several recombinational mechanisms of cointegration with other plasmids that can be followed by imprecise resolution (Zakharova et al., 2002; Bui et al., 2006; Tran et al., 2012; Lin et al., 2013; Ramirez et al., 2014a; He et al., 2015; Cameranesi et al., 2018). Recent studies also showed that multicopy plasmids promote evolution by permitting the coexistence of novel and ancestral traits when a new variant arises through mutation, allowing bacteria to escape the evolutionary constraints imposed by the trade-offs that otherwise would limit the perpetuation of certain gene changes (Rodriguez-Beltran et al., 2018). Furthermore, the usual higher copy number of small plasmids may facilitate the enhancement of resistance levels by gene dosage (Tolmasky et al., 1988; Sandegren and Andersson, 2009).

The pJHCMW1 Plasmid

The most studied K. pneumoniae plasmids are those that code for the complete conjugation machine, virulence factors, and mobile elements (de Toro et al., 2014). They are usually larger than 30-kb and can reach several hundred kb. Smaller K. pneumoniae plasmids, ∼25-kb or less, have attracted much less attention and the majority of the studies are limited to the analysis of their nucleotide sequences and a few complementary experiments. A notable exception is pJHCMW1, isolated from K. pneumoniae JHCK1, which caused several fatalities in a neonatal ward as a consequence of resistance to the antibiotic treatment (Tolmasky et al., 1986; Woloj et al., 1986; Xie et al., 2013). The pJHCMW1 plasmid includes the transposon Tn1331 (nucleotides 3362-11654) and a 3361-nucleotides region that contains the genetic traits specific to inheritance and conjugation (Figure 1A) (Dery et al., 1997; Sarno et al., 2002). A BLAST analysis of this region showed homology to several plasmids. However, the homology was mostly confined to the ColE1-type replication region (Figure 2A) (Pasquali et al., 2005; Tolmasky et al., 2010; Ye et al., 2010; Fricke et al., 2011; Sun et al., 2013; Brantl, 2014; Porres-Osante et al., 2014; Calva et al., 2015; Cao et al., 2015; Lilly and Camps, 2015; Liu et al., 2015). The pJHCMW1 plasmid includes a functional oriT but lacks the genes coding for the relaxosome and the transferosome (Dery et al., 1997) (Figure 1A). Since K. pneumoniae strains usually harbor numerous plasmids, pJHCMW1 may occasionally be transferred to other strains when one or more co-resident plasmids contribute the appropriate helper functions. This was confirmed in a mobilization assay using a recombinant clone, pROXT1, generated by inserting the pJHCMW1 oriT region into pUC4K, and pRK2073 (Leong et al., 1982), a plasmid that includes the whole RK2 conjugation machinery. In a triparental mating including a recipient E. coli and E. coli strains carrying pROXT1 or pRK2073, the transfer frequencies of both plasmids were of the same order (1 and 3.3 × 10^–1, respectively) (Dery et al., 1997). This experiment showed that if the appropriate machinery is coded for by another resident plasmid, pJHCMW1 can be mobilized in trans at frequencies comparable to those of the self-transmissible helper plasmid. Until recently, it was considered unusual that mobilizable plasmids include an oriT but not the genes coding for the specific relaxosome components. However, recent work on conjugation and mobilization of staphylococcal plasmids showed that many, some of them smaller than 5-kb, are transferred by relaxase-in trans mobilization, as it is the case for pJHCMW1 (O’Brien et al., 2015). Further studies showed that a large percentage of S. aureus plasmids include oriT mimics indicating that the number of plasmids with mobilization capabilities may be much higher than initially thought (Ramsay et al., 2016). The pJHCMW1 plasmid also possesses a Xer site-specific recombination site, mwr, which was thoroughly characterized (Figure 1A) (Tolmasky et al., 2000; Pham et al., 2002; Bui et al., 2006; Trigueros et al., 2009; Tran et al., 2010; Ramirez et al., 2014a). Xer site-specific recombination sites play roles in different processes like plasmid stability by promoting dimer resolution or plasmid evolution by formation and resolution of cointegrates and promoting integration of resistance genes and mobile elements (Zakharova et al., 2002; D’Andrea et al., 2009; Merino et al., 2010; Tran et al., 2012; Das et al., 2013; Midonet and Barre, 2014, 2016; Boyd et al., 2017; Cameranesi et al., 2018). They also participate in processes not involving plasmids such as chromosome dimer resolution or integration of IMEXs (integrative mobile elements exploiting Xer) (Barre et al., 2001; Sherratt et al., 2001; Midonet and Barre, 2014, 2016; Midonet et al., 2019).

FIGURE 1

FIGURE 2

While the partition systems required to ensure proper segregation of low copy number plasmids have been thoroughly studied in numerous systems (Baxter and Funnell, 2015), small high copy number plasmids received scarce attention because it was thought that random diffusion was sufficient to avoid generating plasmidless cells after cytokinesis. Few reports are available, and they all have in common that most plasmid molecules are located in the nucleoid-free regions. Localization of pJHCMW1, which has a calculated copy number of 24 when cells are about to divide, using fluorescence microscopy showed that while the bulk of the fluorescence was localized at the poles in nucleoid-free spaces, the shape and position of the fluorescent spots changed over time suggesting that the molecules were only partially restricted to the cell poles (Reyes-Lamothe et al., 2014). Furthermore, when the nucleoid-free spaces were increased using a mutant or treating wild-type cells with cephalexin, the fluorescence occupied all the space suggesting that most molecules are excluded from the chromosomal DNA mass in the nucleoid, pushing them to regions of low chromosomal density (Figure 1B) (Reyes-Lamothe et al., 2014). This process is similar to the exclusion suffered by ribosomes (Robinow and Kellenberger, 1994), whose diameter of gyration – a measure of the size of a polymer, numerically defined as the average of the squared distance of a point in a polymer from its center of mass – is significantly smaller (18 nm) than that of pJHCMW1 (265 nm) (Willumeit et al., 1997; Reyes-Lamothe et al., 2014). It was concluded that pJHCMW1 segregates by random diffusion but with most molecules occupying the nucleoid-free polar regions of the cell. Other studies found high copy number plasmids clustered at the cell poles or combining some molecules randomly distributed throughout the cell and some others clustered (Pogliano et al., 2001; Yao et al., 2007; Wang et al., 2016; Standley et al., 2019). Also, the possibility of active partition has been considered (Million-Weaver and Camps, 2014). However, it should be noted that some of these latter studies were carried out with plasmids with non-natural replicons such as pUC19. This is a derivative of the ColE1-type pMB1 replicon but in which the rom gene has been deleted, and a nucleotide substitution within RNA II alters its spatial structure in a temperature-dependent manner affecting the interaction between RNA II and the negative regulator RNA I (Minton et al., 1988; Lin-Chao et al., 1992). As a consequence, plasmids with this origin of replication have a copy number abnormally higher. This fact could be responsible for anomalous behavior of the plasmids. Nevertheless, all observations are consistent with plasmid localization by random diffusion and nucleoid exclusion. Future studies on other small plasmids will contribute to the understanding of their partition dynamics.

Identification of Completely Sequenced Small K. pneumoniae Plasmids

A search for K. pneumoniae in the NCBI genome database¹ following the link “Plasmid annotation report² ” produced 172 plasmid sequences 25-kb or smaller. After further analysis of these sequences, those that had the same number of nucleotides and showed higher than 99% identity were considered to be the same plasmid (Table 1). The replication regions of pJHCMW1, pKPN2, pKlebB-k17/80, pIP843, pH205, pColEST258, and p15S had been characterized and shown to belong to the ColE1-type (Ramirez et al., 2014a). Alignment of the nucleotide sequences of these regions showed high conservation with three sectors with variability (nucleotides 182-208, 402-439, 565-609, Supplementary Figure S1A). Maximum divergence was estimated at 0.446 substitutions per site (Supplementary Figure S1B). Then, the replication regions of all plasmids were compared to the nucleotide sequences of the replication regions of each one of the seven plasmids named above. Among 172 plasmids, those that showed 50% or higher identity to at least one of the seven plasmids, were considered to possess a ColE1-type replication region (Table 1). Besides, some plasmids did not show 50% or more identity to the replication regions of either of the seven plasmids used as reference, but they are identified as ColE1-type in GenBank. These plasmids are also considered ColE1-type in Table 1. Other plasmids include putative replication proteins in the GenBank annotations, which suggest initiation of replication mechanism other than ColE1-type (Table 1). In a few other cases there are no indications of the replication mechanism, and in one case both a ColE1-type element and a potential replication protein have been identified (Table 1). The information shown in Table 1 indicates that there is a prevalence of the ColE1-type initiation of replication mechanism among sequenced small K. pneumoniae plasmids. To get insights into the evolutionary history of the small plasmids, an alignment-free sequence comparison among its complete sequence were done using Kmacs (Leimeister and Morgenstern, 2014). Subsequently, a hierarchical cluster analysis of studied plasmids was done based on the estimated symmetric distance (Supplementary Figure S2). The results suggest that the seven reference plasmids, pJHCMW1, pKPN2, pKlebB-k17/80, pIP843, pH205, pColEST258, and p15S, represent different lineages of the clustering or “subtypes.” The distributions on the clustering of key mobile elements, and resistance genes indicate that they seem to be shared mainly by two of the three “basal” clusters (Table 1), with only a few exceptions. These similarities may reflect vertical inheritance of the shared genes, however, since clustering method is not independent of gene composition we do not continue discussing this issue in order to avoid tautological thinking.

Antibiotic Resistance Genes and Their Inclusion Within Mobile Elements

The presence of antibiotic resistance genes and mobile elements were searched using the Multiple Antibiotic Resistance Annotator (MARA) and database (Partridge and Tsafnat, 2018) (Table 1). Seven plasmids include genes coding for KPC enzymes while three and one carry genes coding for CMY and CTX-M enzymes, respectively (Table 1). The bla_CMY genes are located adjacent to insertion sequences, ISEcp1 in two cases and ISEcp1:ISKpn26 in another (Table 1) (Verdet et al., 2009). The bla_CTX–M15 gene, present in pIP843, is located between the insertion sequences ISEcp1 and IS903-C, and the bla_KPC genes are associated to Tn4401 or related structures (Table 1) (Cao et al., 2002; Gootz et al., 2009). Five plasmids include bla_OXA–48-like genes. Four of them include bla_OXA–232 and one bla_OXA–181. These genes code for proteins that differ at a single amino acid at position 214, R214 in OXA-181 and S214 in OXA-232 (Potron et al., 2013). These genes are found flanked by ISEcp1 and an incomplete copy of the erythromycin resistance ereA gene, followed by an imperfect second copy of the ISEcp1 right inverted repeat (Table 1) (Potron et al., 2011).

Four plasmids harbor the complete bla_TEM–1 gene, in two of them within a Tn3-like structure and in pNJST258N5 and pJHCMW1 within Tn1331, a transposon described in detail below. The pDMC1097-20.222kb harbors a truncated bla_TEM–1 gene (Figure 2B). This plasmid includes inverted repeated copies of a transposon-like structure that could have been generated after insertion of IS26 within a Tn3-like transposon followed by a recombination process mediated by the insertion sequence (Figure 2B). Analysis of the res region of the mobile elements present in pDMC1097-20.222kb, which includes nucleotides that differ in Tn1, Tn2, and Tn3 (Partridge and Hall, 2005) showed that in one portion the key nucleotides correspond to those in Tn3 and in another one the key nucleotides are those found in Tn2 (see Figure 2C).

The aac(6′)-Ib gene, which can be found in two main variants that differ in one amino acid, L or S (T-329 or C-329, respectively, in Table 1) (Rather et al., 1992; Ramirez and Tolmasky, 2010), was found in two plasmids within a complete copy of Tn1331 (pJHCMW1) and a transposon with 99% identity with Tn1331 (pNJST258N5) and in 21 plasmids within Tn1331 derivatives associated to IS26 (see below). The aac(6′)-Ib gene codes for an acetyltransferase that mediates resistance to numerous aminoglycosides including amikacin (variant T-329) or gentamicin (variant C-329) (Ramirez et al., 2013). This gene, originally identified as part of the transposon Tn1331 within pJHCMW1 (Figure 1) and the Serratia marcescens pAZ007 (Tolmasky et al., 1986; Woloj et al., 1986; Tolmasky and Crosa, 1987; Tran van Nhieu and Collatz, 1987; Nobuta et al., 1988; Partridge, 2015), is the most prevalent in amikacin-resistant Gram-negative clinical isolates and as such it has been the subject of numerous studies to characterize the AAC(6′)-Ib enzyme and to inhibit its effects (Shmara et al., 2001; Pourreza et al., 2005; Lombes et al., 2008; Maurice et al., 2008; Vetting et al., 2008; Soler Bistue et al., 2009; Lin et al., 2014; Li et al., 2015; Lopez et al., 2015; Chiem et al., 2016, 2018; Tran et al., 2018). It may be worthwhile to mention the finding in a K. pneumoniae isolate of a variant of Tn1331, Tn6238, that includes the aac(6′)-Ib-cr gene, which has two nucleotide changes and codes for an enzyme form that catalyzes acetylation of ciprofloxacin (Quiroga et al., 2015). The only other completely sequenced K. pneumoniae plasmid 25-kb or smaller that includes a close relative to Tn1331 (99% identity, called Tn1331 in this review) in its structure is pNJST258N5, recently found in a carbapenem-resistant sequence type (ST) 258 isolate from a patient with urinary tract infection (Chen et al., 2014b; Deleo et al., 2014). A comparison of the pJHCMW1 and pNJST258N5 sequences shows that although they share the Tn1331 transposon, their backbones share homology only at the replication regions and Xer site-specific recombination sites (Figure 2D). Furthermore, these DNA regions are found in opposite orientations with respect to Tn1331. These structural properties suggest that both plasmids were generated independently by insertion of Tn1331 into two different plasmids. The transposon Tn1331 is a derivative of Tn3 with the addition of a segment including three resistance genes, aac(6′)-Ib (also known as aacA4), ant(3^″)-Ia (also known as aadA1) (Ramirez and Tolmasky, 2010), and bla_OXA–9. This region is flanked by 520-bp direct repeats and its structure resembles the variable region of integrons (Tolmasky, 1990; Tolmasky and Crosa, 1993; Ramirez et al., 2008). A detailed description of this segment has been included in previous articles (Tolmasky, 2000; Sarno et al., 2002; Ramirez et al., 2008; Ramirez and Tolmasky, 2010). A derivative of Tn1331, named Tn1331Δ:IS26, that has an insertion of IS26 and a deletion that includes part of ant(3^″)-Ia, the complete bla_OXA–9, and part of bla_TEM–1 (Figure 2E) was first described in pAAC154, and it was later found in several plasmids (Table 1) (Warburg et al., 2012; He et al., 2016). Interestingly, in most cases, the usual flanking direct repeats at the sites of insertion of Tn1331Δ:IS26 are missing, probably due to IS26-mediated processes (Iida et al., 1984; Dawes et al., 2010; Harmer and Hall, 2015; He et al., 2015). A truncated version of Tn1331Δ:IS26 that lacks the region encompassing IS26 and the terminal fraction of Tn1331 was found in the 11,984-nucleotide pBK13043-3 (Table 1 and Figure 2E). The recently described precise excision process mediated by IS26 is probably responsible for the generation of the structure found in this plasmid (Harmer and Hall, 2015). The aac(6′)-Ib gene was also found associated with other Tn3 and IS26 structures (see Table 1). Although other derivatives of Tn1331 were identified (Tolmasky et al., 1988; Poirel et al., 2006; Rice et al., 2008), none of these elements were detected in fully sequenced K. pneumoniae plasmids 25-kb or smaller.

Concluding Remarks

Plasmids are known to host genes coding for virulence factors and antibiotic resistance. These genes are usually located within elements that disseminate at the molecular level. As a consequence, the interplay between dissemination between DNA molecules and the ability of plasmids to disseminate at the cellular level practically erase all barriers for genes to reach virtually all bacteria. Recent research about the genetic characteristics of K. pneumoniae pathogenic strains shows that this bacterium usually harbors numerous plasmids that can shape its properties as well as the nature of the diseases caused. However, within the variety of plasmids found in this bacterium, most of the attention has been directed to large plasmids that can accumulate numerous genetic determinants, mobile elements, and the information of self-transmission. A revision of the information available shows that smaller plasmids, which tend to possess higher copy numbers, can also be active participants in shaping K. pneumoniae strains and their evolution. They can disseminate at the cellular level by mobilization, contribute to plasmid evolution, and enhance gene expression by gene dosage. Despite the small size and limited number of genes they harbor, important resistance genes are usually present in most instances as part of transposons and integron-like structures. All these properties make them important contributors to shaping the biological properties of K. pneumoniae and other bacteria of interest to human health including multidrug resistance.

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