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. 2018 Sep 24;62(10):e01202-18. doi: 10.1128/AAC.01202-18

Impact of Inducible blaDHA-1 on Susceptibility of Klebsiella pneumoniae Clinical Isolates to LYS228 and Identification of Chromosomal mpl and ampD Mutations Mediating Upregulation of Plasmid-Borne blaDHA-1 Expression

Adriana K Jones a,#, Srijan Ranjitkar a,*,#, Sara Lopez a, Cindy Li a, Johanne Blais a, Folkert Reck a, Charles R Dean a,✉
PMCID: PMC6153798  PMID: 30061296

Twenty-three Klebsiella pneumoniae (blaDHA-1) clinical isolates exhibited a range of susceptibilities to LYS228, with MICs of ≥8 μg/ml for 9 of these. Mutants with decreased susceptibility to LYS228 and upregulated expression of blaDHA-1 were selected from representative isolates.

KEYWORDS: DHA-1, Klebsiella, LYS228, beta-lactamases, peptidoglycan, plasmid

ABSTRACT

Twenty-three Klebsiella pneumoniae (blaDHA-1) clinical isolates exhibited a range of susceptibilities to LYS228, with MICs of ≥8 μg/ml for 9 of these. Mutants with decreased susceptibility to LYS228 and upregulated expression of blaDHA-1 were selected from representative isolates. These had mutations in the chromosomal peptidoglycan recycling gene mpl or ampD. Preexisting mpl mutations were also found in some of the clinical isolates examined, and these had strongly upregulated expression of blaDHA-1.

TEXT

Resistance to β-lactams often results from the expression of ever-evolving serine β-lactamase enzymes (SBLs) that degrade penicillins, cephalosporins, monobactams, and, in some cases, carbapenems (1). Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly regarded as a public health issue (2, 3). β-Lactamase inhibitors (BLIs) counter the effect of SBLs, but metallo-β-lactamases (MBLs) such as New Delhi metallo-β-lactamase-1 (NDM-1), usually expressed together with SBLs, have emerged in Klebsiella pneumoniae and Escherichia coli (4). No inhibitors of MBLs are currently available clinically (5). The monobactam aztreonam (ATM) is stable to MBLs (6, 7) but not all SBLs. To address this, the combination of ATM with the β-lactamase inhibitor avibactam (AVI) is currently in clinical trials (ClinicalTrials registration no. NCT01689207).

We designed the monobactam LYS228, now in phase II clinical trials (ClinicalTrials registration no. NCT03354754), that is stable to both MBLs and SBLs (8). Accordingly, the MIC90 of LYS228 was 1 μg/ml against 271 Enterobacteriaceae clinical isolates, including those expressing a variety of β-lactamases (9). The MIC90 of LYS228 was 1 μg/ml against the 81 K. pneumoniae isolates included in that panel (9). Four of the 81 were annotated as having the class C β-lactamase blaDHA-1. Of these, one was found to have a truncation of the blaDHA-1 gene (data not shown). Of the other three, two were susceptible to LYS228 (NB29263 and NB29289, MIC of 0.125 to 0.5) (Table 1), but one was less susceptible (NB29293, mode MIC of 4 μg/ml) (Table 1). K. pneumoniae lacks a chromosomal ampC but can acquire class C genes (e.g., blaDHA-1) on large plasmids. Isolates with plasmid-borne blaDHA-1 have been reported in several geographic locations (10–24). Plasmid-borne blaDHA-1 likely originated from the chromosome of Morganella morganii and carries with it the associated ampR gene, making it inducible (25, 26). Inducible blaDHA-1 itself may not significantly affect susceptibility to many β-lactams, but combined with other mechanisms, such as porin defects (e.g., OmpK35 and/or OmpK36 in K. pneumoniae), it can become more important in some isolates (27, 28). These factors can complicate susceptibility testing for β-lactams, and a lack of robust methodology for identifying these isolates may result in underestimating their prevalence (19, 29–31). To explore if the variable impact of blaDHA-1 on susceptibility extended to LYS228, we expanded our panel to 23 K. pneumoniae clinical isolates, all having blaDHA-1 (among other enzymes), and determined if this panel trended toward decreased LYS228 susceptibility. The isolates originated in the United States (n = 1), Europe (n = 5), the Middle East (n = 3), and the Asia-Pacific (n = 13). The presence of the ampR-blaDHA-1 region was confirmed for all isolates by PCR and sequencing, although strain NB29381 had a C-to-A mutation 37 bp upstream of blaDHA-1 and NB29390 had an A-to-T mutation 74 bp upstream of blaDHA-1. A range of susceptibilities to LYS228 was observed (0.125 to >64 μg/ml) (Table 1), but the LYS228 MIC was ≥8 μg/ml for 9 of the strains. Therefore, although some isolates were susceptible to LYS228, the panel was overall significantly less susceptible than the set of K. pneumoniae isolates that were not selected based on the presence of blaDHA-1 (9). We partially characterized two strains from this panel that had different susceptibilities to LYS228. K. pneumoniae NB29293 susceptibility was variable, with MICs ranging from 2 to 16 μg/ml, consistent with inducibility of blaDHA-1 (mode MIC, 4 μg/ml) (Table 1). Addition of avibactam (4 μg/ml) improved the LYS228 MIC to 0.25 μg/ml (Table 1). An intact ompK35 porin gene could not be amplified by PCR, and the ompK36 porin gene encoded multiple alterations to the porin protein relative to the reference strain ATCC 43816 (32 and data not shown). These defects may be additive with the effect of the inducible DHA-1, as suggested in previous reports. A second isolate, NB29289, was consistently more susceptible to LYS228 than NB29293 (MIC of 0.125 μg/ml) (Table 1). In contrast to strain NB29293, the genes encoding OmpK35 and OmpK36 only had silent mutations compared to reference strain ATCC 43816 (32). This may explain in part why NB29289 is more sensitive to LYS228 than NB29293, but this remains to be confirmed.

TABLE 1.

Antibiotic susceptibilities of K. pneumoniae clinical isolates harboring blaDHAa

Strain Annotated β-lactamase(s)b and relevant mutations MICc μg/ml
LYS228 LYS228/AVI ATM ATM/AVI CAZ FEP MEM
NB29263 DHA-1 0.5 ≤0.06 2 0.25 32 0.125 0.25
NB29289 SHV-31, DHA-1, VIM-1 0.125 ≤0.06 1 0.25 >64 >16 8
NB29289-CDK0033 NB29289 mpl (1-bp deletion, position 45), selected on LYS228 32 0.25 >64 8 >64 >16 8
NB29289-CDK0034 NB29289 mpl (1-bp deletion, position 275), selected on LYS228 8 ≤0.06 >64 1 >64 >16 >8
NB29293 SHV-12, CTX-M-15, DHA-1 4 0.25 >64 1 >64 >16 0.5
NB29338 SHV-OSBL(b), DHA-1; mpl (ΔARHVGVLPADAA290–302) 32 0.125 >64 0.25 >64 1 2
NB29352 SHV-OSBL(b), DHA-1; mpl (ΔAEV397–399, LAQKAAAAE*439–448 to RVRLRSLPSA*) >64 1 >64 1 >64 16 4
NB29353 SHV-OSBL(b), TEM-OSBL(b), DHA-1; mpl (G68D) >64 ≤0.06 >64 ≤0.06 >64 16 1
NB29354 SHV-12(e), DHA-1 64 ≤0.06 >64 ≤0.06 >64 32 8
NB29379 SHV-OSBL, TEM-OSBL; DHA-1 1 ≤0.06 8 0.125 >64 0.125 0.06
NB29380 SHV-OSBL, TEM-OSBL; DHA-1 0.25 0.125 0.5 0.25 1 0.125 0.03
NB29381 SHV-OSBL, DHA-1 2 0.125 16 0.25 64 0.125 0.06
NB29382 SHV-OSBL, DHA-1 2 0.25 8 0.125 >64 0.5 0.125
NB29383 SHV-OSBL, TEM-OSBL; DHA-1 2 ≤0.06 4 0.125 32 0.25 0.06
NB29384 SHV-OSBL, TEM-OSBL; DHA-1 1 ≤0.06 4 0.25 32 0.125 0.06
NB29385 SHV-OSBL, DHA-1 8 0.25 32 0.5 16 4 0.25
NB29386 SHV-OSBL, DHA-1 8 0.25 32 0.5 >64 0.25 0.06
NB29387 SHV-OSBL, DHA-1 0.5 0.125 32 0.125 32 0.125 0.06
NB29388 SHV-OSBL, TEM-OSBL; DHA-1; mpl (D63G) 1 ≤0.06 2 0.25 64 0.125 0.125
NB29389 SHV_OSBL, TEM-OSBL; DHA-1 32 ≤0.06 64 1 >64 1 0.06
NB29390 SHV-OSBL, DHA-1 8 ≤0.06 64 0.5 >64 1 0.125
NB29391 SHV-OSBL, DHA-1 4 0.25 8 0.25 64 1 0.06
NB29392 SHV-OSBL, DHA-1 1 ≤0.06 4 0.125 16 ≤0.06 0.06
NB29393 TEM-OSBL, DHA-1; mpl (G to A, 14 bp upstream of ATG, K131Q, L263F, V432stop) 32 0.125 >64 1 >64 1 0.125
NB29293-CDK0021 NB29293 mpl (D31N), selected on LYS228 >64 0.25 >64 4 >64 >16 0.5
NB29293-CDK0022 NB29293 mpl (W247*), selected on LYS228 >64 0.125 >64 4 >64 16 0.25
NB29289-CDK0036 NB29289 ampD (W7G), selected on LYS228 16 ND >32 ND >32 ND 4
NB29394 DHA-1 4 0.125 16 0.5 64 0.25 0.125
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a

All strains obtained were from International Health Management Associates (IHMA) except for NB29263 (Novartis collection). AVI, avibactam; CAZ, ceftazidime; FEP, cefepime; MEM, meropenem; ND, not determined.

b

β-Lactamase annotations are from IHMA. OSBL, original-spectrum β-lactamase. The ampR-blaDHA-1 region was confirmed here by PCR.

c

AVI used at a fixed concentration of 4 μg/ml. Susceptibility testing was performed using a broth microdilution methodology of the CLSI (41).

Consistent with DHA-1 affecting susceptibility to LYS228, mutants with constitutive upregulation of blaDHA-1 could be selected from strain NB29293 in vitro at a frequency of approximately 10−6 by plating cells on LB agar containing 32 μg/ml of LYS228 (8× the mode MIC). Mutant susceptibility was shifted at least 32-fold (MIC of >64 μg/ml). LYS228 activity was restored by the addition of 4 μg/ml avibactam, confirming involvement of a β-lactamase (NB29293-CDK0022) (Table 1). Genome sequencing of NB29293-CDK0022 using previously described methodology (33) revealed a premature stop codon (encoding W247*) in the chromosomal murein-peptide-ligase gene mpl, which was also present in several other mutants. An NB29293 mutant recovered from a time-kill regrowth experiment, conducted as previously described (9) (NB29293-CDK0021; Table 1), harbored a mutation in mpl encoding D31N. These mutants were constitutively upregulated for expression of blaDHA-1 (Fig. 1). Mutants were also selected from the more sensitive strain NB29289 on agar containing 1 μg/ml LYS228. Of six mutants tested, four had a 1-bp deletion (frameshift) at position 45 and one had a 1-bp deletion at position 275 of mpl. The MIC of LYS228 increased to 8 and 32 μg/ml for these mutants (NB29289-CDK0033 and CDK0034) (Table 1), and again LYS228 susceptibility was restored by the addition of avibactam (Table 1). It should be noted that no mpl mutations were isolated from several non-blaDHA-1 K. pneumoniae isolates during single-step selections described in an accompanying report (33), strengthening the association of mpl mutations with blaDHA-1. Mpl is UDP-N-acetylmuramate:L-alanyl-γ-d-glutamyl-meso-diaminopimelate ligase, involved in peptidoglycan recycling (34, 35), and its mutational loss may induce expression of blaDHA-1 via changes in peptidoglycan intermediates sensed by the plasmid-encoded AmpR regulator. Upregulation of ampC expression caused by mutations in peptidoglycan recycling genes such as ampD or ampG in various bacteria with inducible ampC genes is well studied (36, 37). An in vitro transposon mutagenesis study also found insertions in mpl in Pseudomonas aeruginosa causing AmpR-dependent upregulation of chromosomal ampC and reduced susceptibility to β-lactams (38). A recent report also described the emergence of mpl mutations in P. aeruginosa during serial passaging in the presence of aztreonam (39). The remaining NB29289-derived mutant had an ampD encoding a previously reported W7G substitution shown to upregulate chromosomal ampC expression in some Gram-negative bacteria (40). The MIC of LYS228 increased to 16 for this mutant (Table 1).

FIG 1.

FIG 1

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Constitutive blaDHA-1 expression in mpl mutants selected in vitro from K. pneumoniae NB29293 (NB29293-CDK0021 and NB29293-CDK0022) and in clinical isolates harboring alterations in mpl (NB29338, NB29352, NB29353, and NB29393). RT-qPCR was done as previously described (33), and expression analysis was done using the 2−ΔΔCT method (42) relative to uninduced strain NB29293. Two additional clinical isolates harboring wild-type mpl (NB29263 and NB29379) are included for comparison. Data are averages from two biological replicates. Induction of blaDHA-1 transcription (3- to 7-fold) was seen for NB29293 cells exposed to LYS228 at a MIC of 1 μg/ml (data not shown).

The majority of the clinical isolates studied here encoded an Mpl protein identical to that of reference strain ATCC 43816 (32), which does not harbor blaDHA-1. However, isolate NB29353 encoded MplG68D, and mpl from isolates NB29338, NB29352, and NB29393 contained large deletions, frame shifts, and amino acid substitutions (Table 1). Expression of blaDHA-1 was upregulated 90-fold in NB29338 and >300-fold in NB29352, NB29353, and NB29393 relative to strains NB29293, NB29263, and NB29379, which all harbored wild-type mpl (Fig. 1). NB29338, NB29352, NB29353, and NB29393 were also among the least susceptible to LYS228 of the blaDHA-1-containing K. pneumoniae strains tested (Table 1).

In conclusion, this study suggests that inducible blaDHA-1 can decrease susceptibility to LYS228 in some K. pneumoniae clinical isolates, presumably depending on the presence of additional resistance mechanisms in these strains. In cases where β-lactamases may impact the clinical utility of LYS228, pairing with an appropriate β-lactamase inhibitor may restore susceptibility. We also uncovered a novel mechanism of upregulation of plasmid-borne blaDHA-1 expression via chromosomal mpl mutations and show that these mutations occur in clinical isolates. To our knowledge, this is the first report of this mechanism in K. pneumoniae. Delineating the mechanism by which defects in Mpl upregulate DHA-1 expression warrants further study.

ACKNOWLEDGMENTS

We thank Dave Barkan and Peter Skewes-Cox for bioinformatics assistance and Daryl Richie for helpful discussion.

Footnotes

For a companion article on this topic, see https://doi.org/10.1128/AAC.01200-18.

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