Antimicrobial Resistance in Pasteurellaceae of Veterinary Origin

Abstract

Members of the highly heterogeneous family Pasteurellaceae cause a wide variety of diseases in humans and animals. Antimicrobial agents are the most powerful tools to control such infections. However, the acquisition of resistance genes, as well as the development of resistance-mediating mutations, significantly reduces the efficacy of the antimicrobial agents. This article gives a brief description of the role of selected members of the family Pasteurellaceae in animal infections and of the most recent data on the susceptibility status of such members. Moreover, a review of the current knowledge of the genetic basis of resistance to antimicrobial agents is included, with particular reference to resistance to tetracyclines, β-lactam antibiotics, aminoglycosides/aminocyclitols, folate pathway inhibitors, macrolides, lincosamides, phenicols, and quinolones. This article focusses on the genera of veterinary importance for which sufficient data on antimicrobial susceptibility and the detection of resistance genes are currently available (Pasteurella, Mannheimia, Actinobacillus, Haemophilus, and Histophilus). Additionally, the role of plasmids, transposons, and integrative and conjugative elements in the spread of the resistance genes within and beyond the aforementioned genera is highlighted to provide insight into horizontal dissemination, coselection, and persistence of antimicrobial resistance genes. The article discusses the acquisition of diverse resistance genes by the selected Pasteurellaceae members from other Gram-negative or maybe even Gram-positive bacteria. Although the susceptibility status of these members still looks rather favorable, monitoring of their antimicrobial susceptibility is required for early detection of changes in the susceptibility status and the newly acquired/developed resistance mechanisms.

FIGURE 1

Schematic representation of the structure and organization of genes found in tet(H)-carrying plasmids from P. multocida, M. haemolytica, [P.] aerogenes, and A. pleuropneumoniae. Comparison of the maps of the partially sequenced plasmids pPMT1 (accession no. Y15510) and pVM111 (accession nos. AJ514834 and U00792), both from P. multocida, pMHT1 (accession no. Y16103) from M. haemolytica, and pPAT1 (accession no. AJ245947) from [P.] aerogenes (accession no. Z21724) and the completely sequenced plasmids p9956 (accession no. AY362554; 5,674 bp) and p12494 (accession no. DQ517426; 14,393 bp), both from A. pleuropneumoniae. Genes are shown as arrows, with the arrowhead indicating the direction of transcription. The following genes are involved in antimicrobial resistance: tetR-tet(H) (tetracycline resistance), sul2 (sulfonamide resistance), and strA and strB (streptomycin resistance); plasmid replication: repB; mobilization functions: mobA, mobB, mobC, and mobA_L; recombination functions: rec; DNA partition: par; virulence: vapD and vapX; unknown function: the open reading frame indicated by the white arrow. The Δ symbol indicates a truncated functionally inactive gene. The white boxes in the maps of pPMT1 and p12494 indicate the limits of the insertion sequences IS1592, IS1596, and IS1597; the arrows within these boxes indicate the reading frames of the corresponding transposase genes. Gray shaded areas indicate the tetR-tet(H) gene region common to all these plasmids with ≥95% nucleotide sequence identity. A distance scale in kilobases is shown at the bottom of the figure.

FIGURE 2

Schematic representation of the structure and organization of aadA14-, tet(L)-, and tet(B)-carrying plasmids from P. multocida, M. haemolytica, [H.] parasuis, [P.] aerogenes, and A. pleuropneumoniae. Comparison of the maps of the aadA14-carrying streptomycin/spectinomycin resistance plasmid pCCK647 (accession no. AJ884726; 5,198 bp) from P. multocida, the tet(L)-carrying tetracycline resistance plasmid pCCK3259 (accession no. AJ966516; 5,317 bp) from M. haemolytica, and the tet(B)-carrying tetracycline resistance plasmids pHS-Tet (accession no. AY862435; 5,147 bp) from [H.] parasuis, pPAT2 (accession no. AJ278685; partially sequenced) from [P.] aerogenes, p11745 (accession no. DQ176855; 5,486 bp) from A. pleuropneumoniae, pHPS1019 (accession no. HQ622101; 4,597 bp) from [H.] parasuis, and pB1001 (accession no. EU252517; 5,128 bp) from P. multocida. Genes are shown as arrows, with the arrowhead indicating the direction of transcription. The following genes are involved in antimicrobial resistance: tetR-tet(B), tet(B), and tet(L) (tetracycline resistance) and aadA14 (streptomycin/spectinomycin resistance); plasmid replication: rep; mobilization functions: mobA, mobB, and mobC; unknown function: the open reading frames indicated by white arrows. Gray-shaded areas indicate the regions common to plasmids, and the different shades of gray illustrate the percentages of nucleotide sequence identity between the plasmids, as indicated by the scale at the bottom of the figure. A distance scale in kilobases is shown.

FIGURE 3

Schematic representation of the structure and organization of the bla_ROB-1-carrying resistance plasmids from M. haemolytica, [H.] parasuis, P. multocida, A. pleuropneumoniae, and “A. porcitonsillarum.” Comparison of the maps of bla_ROB-1-carrying resistance plasmids pAB2 (accession no. Z21724; 4,316 bp) from M. haemolytica, pB1000 (accession no. DQ840517; 4,613 bp) from [H.] parasuis, pB1002 (accession no. EU283341; 5,685 bp) from P. multocida, APP7_A (accession no. CP001094; 5,685 bp) from A. pleuropneumoniae, pIMD50 (accession no. AJ830711; 8,751 bp) from “A. porcitonsillarum,” and pHB0503 (accession no. EU715370; 15,079 bp) from A. pleuropneumoniae. It should be noted that another three pIMD50-related bla_ROB-1-carrying resistance plasmids from “A. porcitonsillarum” have been sequenced completely: pKMA5 (accession no. AM748705), pKMA202 (accession no. AM748706), and pKMA1467 (accession no. AJ830712). Genes are shown as arrows, with the arrowhead indicating the direction of transcription. The following genes are involved in antimicrobial resistance: sul2 (sulfonamide resistance), strA and strB (streptomycin resistance), bla_ROB-1 (β-lactam resistance), aacC2 (gentamicin resistance), catA3 (chloramphenicol resistance), and aphA1 (kanamycin/neomycin resistance); plasmid replication: rep; mobilization functions: mobA, mobB, and mobC; resolvase function: res; DNA partition: parA; unknown function: open reading frames indicated by white arrows. The prefix Δ indicates a truncated functionally inactive gene. Gray-shaded areas indicate the regions common to plasmids, and the different shades of gray illustrate the percentages of nucleotide sequence identity between the plasmids, as indicated by the scale at the bottom of the figure. A distance scale in kilobases is shown.

FIGURE 4

Schematic representation of the structure and organization of selected sul2-based (multi-)resistance plasmids from A. pleuropneumoniae, “A. porcitonsillarum,” A. paragallinarum, H. ducreyi, [H.] parasuis, M. haemolytica, Mannheimia unnamed taxon 10, M. varigena, and P. multocida. Comparison of the maps of the plasmids pKMA2425 (accession no. AJ830714; 3,156 bp) from A. pleuropneumoniae, pARD3079 (accession no. AM748707; 4,065 bp) from A. pleuropneumoniae, pKMA757 (accession no. AJ830713; 4,556 bp) from “A. porcitonsillarum,” ABB7_B (accession no. NC_010941; 4,236 bp) from A. pleuropneumoniae, pIG1 (accession no. U57647) from P. multocida, pYFC1 (accession no. M83717) from M. haemolytica, pFZG1012 (accession no. HQ015158; partially sequenced) from [H.] parasuis, pLS88 (accession no. L23118; 4,772 bp) from H. ducreyi, pYMH5 (accession no. EF015636; 4,772 bp) from A. paragallinarum, pM3224T (accession no. KP197004; 6,050 bp) from A. pleuropneumoniae, pMS260 (accession no. AB109805; 8,124 bp) from A. pleuropneumoniae, pMVSCS1 (accession no. AJ319822; 5,621 bp) from M. varigena, pMHSCS1 (accession no. AJ249249; 4,992 bp) from Mannheimia unnamed taxon 10, pFZ51 (accession no. JN202624; 15,672 bp) from [H.] parasuis, and pKMA757 (accession no. AJ830713; 4,556 bp) from “A. porcitonsillarum.” The map of another sul2-based multiresistance plasmid, pIMD50 (accession no. AJ830711) from “A. porcitonsillarum,” is displayed in Fig. 3. Genes are shown as arrows, with the arrowhead indicating the direction of transcription. The following genes are involved in antimicrobial resistance: sul2 (sulfonamide resistance), strA and strB (streptomycin resistance), catA3 (chloramphenicol resistance), aphA1 (kanamycin/neomycin resistance), and bla_ROB-1 (β-lactam resistance); plasmid replication: rep, repA, repB, and repC; mobilization functions: mobA, mobB, mobC, mobA′, mobB′, and mobC′; unknown function: open reading frames indicated by white arrows. The prefix Δ indicates a truncated functionally inactive gene. Gray-shaded areas indicate the regions common to plasmids and the different shades of gray illustrate the percentages of nucleotide sequence identity between the plasmids, as indicated by the scale at the bottom of the figure. A distance scale in kilobases is shown.

FIGURE 5

Schematic representation of the structure and organization of selected floR-based (multi-)resistance plasmids from B. trehalosi compared to an in-part-related plasmid from [H.] parasuis, and A. pleuropneumoniae, [H.] parasuis, P. multocida, and sul2-based (multi-)resistance plasmids from H. ducreyi and [H.] parasuis. Comparison of the maps of plasmids pCCK13698 (accession no. AM183225) from B. trehalosi and its in-part-related plasmid pHS-Rec (accession no. AY862436; 9,462 bp) from [H.] parasuis, pCCK381 (accession no. AJ871969; 10,874 bp) from P. multocida, pCCK1900 (accession no. FM179941; 10,226 bp) from P. multocida, pHPSF1 (accession no. KR262062; 6,328 bp) from [H.] parasuis, pM3446F (accession no. KP696484; 7,709 bp) from A. pleuropneumoniae, pMh1405 (accession no. NC_019260; 7,674 bp) from M. haemolytica, p518 (accession no. KT355773; 3,937 bp) from A. pleuropneumoniae, pFZG1012 (accession no. HQ015158; partially sequenced) from [H.] parasuis, and pLS88 (accession no. L23118; 4,772 bp) from H. ducreyi. Genes are shown as arrows, with the arrowhead indicating the direction of transcription. The following genes are involved in antimicrobial resistance: sul2 (sulfonamide resistance), strA and strB (streptomycin resistance), catA3 (chloramphenicol resistance), floR (chloramphenicol/florfenicol resistance), and aphA1 (kanamycin/neomycin resistance); plasmid replication: rep, repA, repB, and repC; mobilization functions: mobA, mobB, mobC, and mob; transposition functions: tnp; recombinase or integrase functions: rec and int; DNA partition: parA; unknown function: open reading frames indicated by white arrows. The prefix Δ indicates a truncated functionally inactive gene. The boxes in the map of pCCK13698 indicate the limits of the insertion sequences IS1592 and IS26; the arrows within these boxes indicate the reading frames of the corresponding transposase genes. Gray-shaded areas indicate the regions common to plasmids, and the different shades of gray illustrate the percentages of nucleotide sequence identity between the plasmids, as indicated by the scale at the bottom of the figure. A distance scale in kilobases is shown.