- \n
- Low-affinity<\/strong> PBP \u2013 PBP5 (PBP4 in Enterococcus faecalis) has a low affinity for beta-lactams. Hence, it can continue peptidoglycan synthesis even when other PBPs are saturated. The intrinsic resistance is highest in cephalosporins than in carbapenems. It is lowest in penicillins, including aminopenicillins.<\/li>\n<\/ol>\n\n\n\n
2. Acquired resistance to aminopenicillin \u2013 85-90% of Enterococcus faecium and a small number of Enterococcus faecalis are resistant to amoxicillin. It is because of:<\/p>\n\n\n\n
- \n
- Sequential mutation in the PBP5 <\/strong>gene<\/li>\n\n\n\n
- Bypassing the PBP<\/strong> \u2013 ampicillin-insensitive l,d-transpeptidase, (Ldtfm) \u2013 an alternative enzyme is used instead of PBP in cell wall synthesis. [Sacco, 2014<\/a>].<\/li>\n<\/ul>\n\n\n\n
These mechanisms are common in Enterococcus faecium.<\/p>\n\n\n\n
3.\u00a0Beta-lactamase productio<\/strong>n \u2013 This is more common in Enterococcus faecalis; however, it has been reported in Enterococcus faecium occasionally. It is plasmid-mediated and similar to Staphylococcal beta-lactamase. These organisms are resistant to penicillin and amoxicillin but not to beta-lactam beta-lactamase combinations, for example, co-amoxiclav.<\/p>\n\n\n\n
4. Penicillin-resistant but ampicillin-susceptible E. faecalis<\/em> (PRASEF<\/em>) \u2013 a point mutation in the PBP4<\/strong> is responsible for this phenotype.<\/p>\n\n\n\n
\n\n\n\nGlycopeptide<\/h2>\n\n\n\n
Glycopeptide-resistant Enterococcus are becoming a major antibiotic resistance issue worldwide. These strains are Glycopeptide Resistant Enterococcus (GRE) or Vancomycin-resistant Enterococcus (VRE). Although a specific resistance mechanism may make a strain resistant to vancomycin and not to teicoplanin, the acronym VRE is often used loosely for glycopeptide-resistant Enterococcus.<\/p>\n\n\n\n
Certain clones of VRE are specially adapted to the hospital environment, multidrug-resistant or associated with outbreaks e.g. clonal complex E. faecium<\/em> 17 (CC17).<\/p>\n\n\n\n
The mechanism of action of the glycopeptides is inhibiting cell wall formation. The cell wall is composed of a rigid peptidoglycan layer, which is a polymer of two compounds, N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG). Glycopeptides bind to the D-alanine-D alanine residue of the NAM and prevent cross-linking between two NAM molecules. This results in the prevention of peptidoglycan biosynthesis.<\/p>\n\n\n\n
![\"\"\/](\"https:\/\/upload.wikimedia.org\/wikipedia\/commons\/thumb\/5\/5f\/Vancomycin_resistance.svg\/1920px-Vancomycin_resistance.svg.png\")
Image credit: Mcstrother<\/a>, Wikipedia, CC BY 3.0<\/a>, Image link<\/a><\/em><\/figcaption><\/figure>\n\n\n\n The mechanisms of resistance are \u2013<\/strong><\/p>\n\n\n\n
- \n
- Van gene-mediated resistance\u00a0<\/strong>\u2013 The van gene mutation converts D-Alanine-D-Alanine (D-Ala-D-Ala) to either D-Alanine-D-Lactate (D-Ala-D-Lac) or D- Alanine-D-Serine (D-Ala-D-Ser).
D-Ala-D-Lac has 1000-fold less affinity for glycopeptide, whereas D-Ala-D-Ser has a 7-fold lower affinity.<\/li>\n<\/ol>\n\n\n\nThere are at least nine van genes, classified based on their level of resistance, transferability and inducibility.<\/p>\n\n\n\n
Genotype<\/strong><\/td> Can be found in<\/strong><\/td> Resistant to (phenotype)<\/strong><\/td> Transferrable?<\/strong><\/td><\/tr> Van A<\/td> E faecalis, E faecium<\/td> Vancomycin,
Teicoplanin<\/td>Chromosomal,
Transferrable<\/td><\/tr>Van B<\/td> E faecalis, E faecium<\/td> Vancomycin only
(However, an additional mutation conferring
teicoplanin resistance has been reported)<\/td>Chromosomal,
Transferrable<\/td><\/tr>Van C<\/td> E casseliflavus,
E gallinarum<\/td>Vancomycin only
(intrinsic resistance in these bacteria)<\/td>Chromosomal<\/td><\/tr> Van D<\/td> E faecium
E faecalis
(also found in some E gallinarum)<\/td>Vancomycin,
Teicoplanin (variable)<\/td>Chromosomal<\/td><\/tr> Van E,
Van L<\/td>E faecalis<\/td> Vancomycin only<\/td> Chromosomal<\/td><\/tr> Van G<\/td> E faecalis<\/td> Vancomycin only<\/td> Chromosomal,
Transferrable<\/td><\/tr>Van M<\/td> E faecium<\/td> Vancomycin,
Teicoplanin<\/td>Transferrable<\/td><\/tr> Van N<\/td> E faecium<\/td> Vancomycin only<\/td> Plasmid, transferrable<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n 2. L,d-transpeptida<\/strong>se \u2013 This is a similar mechanism described in the beta-lactam section above. The crosslinking by this enzyme uses precursors without the terminal d-alanine, so glycopeptides cannot prevent this reaction. This is mainly seen in Ent faecium.<\/p>\n\n\n\n
3. Vancomycin-variable enterococci (VVE) <\/strong>\u2013 This is an emerging resistance pattern in E faecium and E faecalis. These strains present with a vancomycin susceptible phenotype but develop resistance rapidly within a few days of exposure to Vancomycin or Teicoplanin. There are different mechanisms that result in the expression of vanHAX genes. Outbreaks have been reported in Canada and European countries.<\/p>\n\n\n\n
\n\n\n\nDaptomycin<\/h2>\n\n\n\n
Epidemiological cut-off (ECOFF) value for E. faecium<\/em> and E. faecalis<\/em> to \u22644\u2009\u03bcg\/ml for daptomycin. The major mechanisms of resistance are \u2013<\/p>\n\n\n\n
- \n
- Activation of liaFSR regulatory system <\/strong>\u2013 This is a cell envelope stress response leading to a decrease in the phosphatidylglycerol content of the cell membrane. It also causes thickening of the cell wall and aberrant septum placement. Cross-resistance has been noted with vancomycin and bacitracin. This system may play a role in diverting the daptomycin from the preferred target on the septum to other areas of the cell membrane.<\/li>\n\n\n\n
- Increase the thickness of the cell wall; altered homeostasis<\/strong> \u2013 yycFG<\/em> [walKR<\/em>]<\/strong> and vraSR<\/em><\/strong> mutation \u2013 thickening of the cell wall, altered homeostasis.<\/em><\/li>\n<\/ul>\n\n\n\n
In addition to these, multiple other mutations may contribute to daptomycin resistance. These are gdpD<\/strong> (Glycerophosphoryl diester phosphodiesterase) and cls <\/strong>(Cardiolipin synthetase). These mutations often act together or in a sequential manner in conferring resistance.<\/p>\n\n\n\n
The resistance is due to these phenotypic changes \u2013<\/p>\n\n\n\n
- \n
- generating a positive charge on the cell membrane to repulse daptomycin<\/li>\n\n\n\n
- cell envelope stress response \u2013 decrease in PG content of cell membrane, thickening of cell wall, aberrant septum formation, diverting the daptomycin from its preferred site of action<\/li>\n\n\n\n
- Increasing the fluidity of the cell membrane<\/li>\n<\/ul>\n\n\n\n
\n\n\n\nLinezolid<\/h2>\n\n\n\n
- \n
- Target site modification due to mutations in domain V of 23S rRNA: There could be multiple mutations, and in Enterococcus, the critical step in the development of resistance is the first mutation. After that, sequential mutation may happen by recombination. Some of the mutations are \u2013 rplC mutation (affecting ribosomal protein L3), rplD gene mutation (affecting L4), and rplV (affecting L22). These mutations are chromosomal.<\/li>\n\n\n\n
- Target site modification by Cfr methyltransferase. It is mediated by the cfr gene. This resistance is transferrable and may give rise to a phenotype called PhLOPSA (resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A). The presence of cfr mutation may not always confer resistance or may confer resistance to linezolid but spare tedizolid.<\/li>\n\n\n\n
- OptrA gene-mediated target protection: optrA encodes for an ATP-binding cassette (ABC)-F protein and mediates resistance through target protection. It is transferrable. There is another similar gene that has been described PoxtA.
These confer resistance to phenicols, linezolid\/tedizolid and tetracyclines.<\/li>\n\n\n\n - Other mechanisms like cell wall thickening, biofilm formation and efflux pumps have been suggested or investigated.<\/li>\n<\/ul>\n\n\n\n
\n\n\n\nTigecycline<\/h2>\n\n\n\n
- \n
- Upregulated efflux pump \u2013 tetL gene-mediated. It increases the number of MFS superfamily efflux pumps.<\/li>\n\n\n\n
- Target protection \u2013 ribosomal protection protein mediated by TetM gene.<\/li>\n\n\n\n
- Target modification \u2013 mutation in ribosomal protein S10, mediated by rpsJ<\/em> gene<\/li>\n<\/ol>\n\n\n\n
\n\n\n\nReference<\/h2>\n\n\n\n
Moon et al, The structures of penicillin-binding protein 4 (PBP4) and PBP5 from Enterococci provide structural insights into \u03b2-lactam resistance, J Biol Chem, . 2018 Nov 30;293(48):18574-18584. doi: 10.1074\/jbc.RA118.006052. Epub 2018 Oct 24.<\/a><\/p>\n\n\n\n
Gagetti et al, Resistance to \u03b2-lactams in enterococciResistencia a los \u03b2-lact\u00e1micos en enterococos, Revista Argentina de Microbiolog\u00eda, Volume 51, Issue 2, April\u2013June 2019, Pages 179-183.<\/a><\/p>\n\n\n\n
Sacco et al, Serine\/Threonine Protein Phosphatase-Mediated Control of the Peptidoglycan Cross-Linking l,d-Transpeptidase Pathway in Enterococcus faecium, ASM Journals, mBio, Vol. 5, No. 4<\/a><\/p>\n\n\n\n
Ahmed and Baptiste, Vancomycin-Resistant Enterococci: A Review of Antimicrobial Resistance Mechanisms and Perspectives of Human and Animal Health, Microbial Drug ResistanceVol. 24, No. 5, 1 Jun 2018https:\/\/doi.org\/10.1089\/mdr.2017.0147<\/a><\/p>\n\n\n\n
- Increase the thickness of the cell wall; altered homeostasis<\/strong> \u2013 yycFG<\/em> [walKR<\/em>]<\/strong> and vraSR<\/em><\/strong> mutation \u2013 thickening of the cell wall, altered homeostasis.<\/em><\/li>\n<\/ul>\n\n\n\n
- Activation of liaFSR regulatory system <\/strong>\u2013 This is a cell envelope stress response leading to a decrease in the phosphatidylglycerol content of the cell membrane. It also causes thickening of the cell wall and aberrant septum placement. Cross-resistance has been noted with vancomycin and bacitracin. This system may play a role in diverting the daptomycin from the preferred target on the septum to other areas of the cell membrane.<\/li>\n\n\n\n
- Bypassing the PBP<\/strong> \u2013 ampicillin-insensitive l,d-transpeptidase, (Ldtfm) \u2013 an alternative enzyme is used instead of PBP in cell wall synthesis. [Sacco, 2014<\/a>].<\/li>\n<\/ul>\n\n\n\n
- Sequential mutation in the PBP5 <\/strong>gene<\/li>\n\n\n\n