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Li, G.;  Walker, M.J.;  Oliveira, D.M.P.D. Vancomycin Resistance in Enterococcus and Staphylococcus aureus. Encyclopedia. Available online: https://encyclopedia.pub/entry/39595 (accessed on 27 November 2024).
Li G,  Walker MJ,  Oliveira DMPD. Vancomycin Resistance in Enterococcus and Staphylococcus aureus. Encyclopedia. Available at: https://encyclopedia.pub/entry/39595. Accessed November 27, 2024.
Li, Gen, Mark J. Walker, David M. P. De Oliveira. "Vancomycin Resistance in Enterococcus and Staphylococcus aureus" Encyclopedia, https://encyclopedia.pub/entry/39595 (accessed November 27, 2024).
Li, G.,  Walker, M.J., & Oliveira, D.M.P.D. (2022, December 30). Vancomycin Resistance in Enterococcus and Staphylococcus aureus. In Encyclopedia. https://encyclopedia.pub/entry/39595
Li, Gen, et al. "Vancomycin Resistance in Enterococcus and Staphylococcus aureus." Encyclopedia. Web. 30 December, 2022.
Vancomycin Resistance in Enterococcus and Staphylococcus aureus
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This entry is adapted from the peer-reviewed paper 10.3390/microorganisms11010024

Enterococcus faecalis, Enterococcus faecium and Staphylococcus aureus are both common commensals and major opportunistic human pathogens. These bacteria have acquired broad resistance to several major classes of antibiotics, including commonly employed glycopeptides. Exemplified by resistance to vancomycin, glycopeptide resistance is mediated through intrinsic gene mutations, and/or transferrable van resistance gene cassette-carrying mobile genetic elements. 

antibiotic vancomycin drug-resistance Enterococcus Staphylococcus aureus

1. Introduction

1.1. Enterococcus faecalis and Enterococcus faecium

The genus Enterococcus are Gram-positive, facultative anaerobic cocci. These bacteria are common commensals of the human gastrointestinal [1] and vaginal tracts, oral cavity [2] and are ubiquitous in nature [3]. In healthy individuals, enterococci can comprise up to 1% of the total bacterial microbiota [4]. Currently, at least 73 different enterococcal species are known [5], with Enterococcus faecalis and E. faecium being the most common species in humans [4]. Enterococci are also opportunistic human pathogens, with E. faecalis and E. faecium demonstrating the highest prevalence of infection; up to 90% of human Enterococcus infections are caused by E. faecalis [6] and the remainder by E. faecium [2], although infections by other Enterococcus species do sporadically occur [7]. As such, E. faecalis and E. faecium will be the focus for this entry.
Enterococci are intrinsically resistant to many antibiotic classes [8]. Mainly driven by selection pressures caused by inappropriate antibiotic stewardship practices [9], enterococci have acquired additional resistance determinants (Figure 1) through both horizontal gene transfer and spontaneous mutations (Table 1) [10]. E. faecalis and E. faecium are responsible for numerous nosocomial infections such as wound and soft-tissue infections, neonatal infections, urinary tract infections, meningitis, bacteremia, sepsis, biofilm-associated infections of medical devices and endocarditis [1][11][12]. In humans, E. faecalis is the species responsible for the majority of enterococcal infections [6] and has been associated with community-associated (CA) diseases of the oral cavity such as periodontitis, peri-implantitis, caries and endodontic infections [13][14][15] as well as bacteremia, while E. faecium is predominantly linked to healthcare-associated (HA) bacteremia [16]. The greater propensity of E. faecalis to cause infections can be attributed to its enhanced capability to acquire and express select virulence factors. In contrast, E. faecium is considered less virulent but with comparatively higher mortality rates in some HA infections such as bacteremia due to its greater disposition for antibiotic resistance [16][17][18][19][20], including vancomycin resistance [8][21][22][23]. This enhances the survivability and persistence of E. faecium within HA settings, allowing it to cause nosocomial infections despite its antibiotic-abundant environment [18][24][25][26][27][28].
Figure 1. Timeline of antibiotic introduction (above) and subsequent resistance emergence in Enterococcus spp (below) [29][30][31][32][33][34]. Abbreviations: GRE—Gentamicin-resistant Enterococcus; PRE—Penicillin-resistant Enterococcus; VRE—Vancomycin-resistant Enterococcus; LRE—Linezolid-resistant Enterococcus; DRE—Daptomycin-resistant Enterococcus.
Table 1. Genetic basis of antibiotic resistance mechanisms in enterococci. There is significant overlap of the numerous different genes and gene mutations implicated in enterococcal and staphylococcal antibiotic resistance (Table 2). Many of these genes are also found on mobile genetic elements (MGEs), which can enable inter- and/or intra-species antibiotic resistance gene transfer [35]. In addition, bacteria can develop/acquire multiple methods of resistance against the same antibiotic class (e.g., mutations in DNA gyrase, topoisomerase IV or the expression of protective proteins or efflux pumps against quinolones). Finally, the expression of one gene may also confer resistance to multiple antibiotic classes (e.g., cfr, optrA).
Antibiotic Class Resistance Gene(s), Family or Operon Protein(s) Produced Mechanism of Action Gene Location(s) Enterococcal Mobile Genetic Elements (MGEs) References
Aminoglycosides aac Acetyltransferase Antibiotic modification and inactivation Chromosome, plasmid, transposon Plasmids (P): pIP800, pJH1, pR538-1, pYN134, Inc. 18

Transposons (T): Tn1546, Tn4001, Tn5281, Tn5382, Tn5385		 [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]
aad,
ant		 Adenylyltransferase Plasmid, transposon
aph Phosphotransferase Plasmid, transposon
efmM Methyltransferase Methylation of 16S rRNA nucleotide; reduction of antibiotic target affinity Chromosome - [56]
Bacitracin, cephalosporins croRS system Penicillin-binding protein 5 (PBP5) and others Cellular signaling in response to cell wall stress; deletion increases cellular susceptibility to antibiotics. Also involved in overexpression of PBP5 Chromosome - [57]
β-lactams blaZ β-lactamase Inactivation of β-lactam antibiotics through enzymatic hydrolysis Chromosome, plasmid, transposon P: pBEM10
T: Tn5385, Tn552		 [45][46][58][59][60][61][62]
Cephalosporin class β-lactams pbp5 Penicillin-binding protein Reduced antibiotic affinity; enables cell wall cross-linking in the presence of β-lactams Chromosome, plasmid, transposon P: The possibility of plasmid-mediated pbp5 transfer has been mentioned. No pbp5-carrying plasmids have been described in E. faecalis or E. faecium, although it has been hypothesized.T: Conjugative transposon CTn5386 [63][64][65][66][67][68][69]
IreK, ireP IreK—Ser/Thr kinaseireP—protein phosphatase Part of a signaling transduction pathway that regulates cephalosporin resistance Chromosome - [70]
Chloramphenicol cat Chloramphenicol
acetyltransferase		 Enzymatic acetylation of chloramphenicol; antibiotic inactivation Plasmid P: pRE25, pRUM, pIP501 [71][72][73][74]
Glycopeptides (e.g., vancomycin) liaFSR, liaXYZ liaFSR is a regulatory system, with liaXYZ proteins being effector proteins Modification of the cell membrane and envelope stress response. Modulates cell membrane localization or content, thus altering the antibiotic target site Chromosome - [75][76]
cls Cardiolipin synthase Involved in cell membrane synthesis; increased cls expression led to membrane modification that impaired antibiotic penetration and activity Chromosome - [77][78][79]
mprF Bifunctional membrane enzyme involved in phospholipid synthesis and translocation Increased positive charge of cell membrane and change of membrane fluidity that reduces antibiotic affinity; target modification Homologs/paralogs described but not extensively studied—gene loci not reported Unknown [80][81]
van operon (e.g., vanA) van operon proteins—refer to Section 2.3 Reduction of antibiotic affinity through cell wall modification Chromosome, plasmid, transposon P: pHKK701, pHKK702, pHK703, pIP816, pIP964, pMG2200, pVEF1

T: Tn1546, Tn1547, Tn1549-like, Tn5482, Tn5506		 [82][83][84][85][86][87][88][89][90][91]
Lincosamides
Oxazolidinones
Phenicols
Pleuromutilins
Streptogramin A		 cfr rRNA methyltransferase Methylation of A2503 bacterial 23S rRNA gene; reduced antibiotic affinity to methylated ribosomes Chromosome,
plasmid, transposon		 P: pEF-01

T: IS1216, Tn6218-like		 [92][93][94]
optrA a ABC-F protein Active dislodgement of antibiotic from its ribosomal target site Chromosome, plasmid, transposon P: Inc18, pE349

T: Tn554, Tn6674		 [95][96][97][98][99]
Linezolid G2576T Point mutation in 23S rRNA gene Ribosomal target modification, reduction of antibiotic affinity Chromosome - [100]
Macrolides
Lincosamides
Streptogramins		 erm Ribosomal methylase Methylation of bacterial 23S rRNA domain V; modification of target site and reduced antibiotic binding affinity Plasmid, transposon P: pLG2, pRUM-like

T: Tn916/Tn1545		 [45][46][58][101][102][103][104][105][106][107][108]
lsa Efflux pump Antibiotic efflux Chromosome, plasmid P: pMG1-like, pXD4, pY13 [109][110][111]
msrA b Chromosome - [112][113]
Phosphonic Acid (e.g., fosfomycin) fosB Fosfomycin inactivating enzyme Mn2+-dependent enzymatic modification and inactivation of fosfomycin Plasmid, transposon, transferable extrachromosomal intermediate P: pEMA120
T: ISL3-like, Tn1546-like		 [114][115][116][117]
Quinolones emeA Efflux pump Antibiotic efflux Chromosome - [118]
gyrA DNA gyrase mutation Reduced antibiotic binding affinity [119][120][121][122]
parC Mutation of topoisomerase IV     [119][121][122]
qnr Pentapeptide repeat protein Protection of DNA gyrase against antibiotic mediated inhibition     [123]
Streptogramin A vat Acetyltransferases Antibiotic modification and inactivation Plasmid P: pAT15, pAT421 [124][125][126][127][128][129][130]
vga Efflux pump Antibiotic efflux Plasmid c - [130]
Tetracyclines tetM, tetO, tetS Ribosome protection protein Binding to bacterial ribosome; interference with tetracycline-ribosome binding Chromosome, plasmid, transposon P: pDO1–like

T: Tn916/Tn1545 family, Tn5397-like		 [45][46][107][108][119][131][132][133][134][135]
tetK, tetL Efflux pump Antibiotic efflux
a Confers resistance to oxazolidinones and phenicols only [99][136]. b Confers resistance to macrolides and streptogramins only [137]. c The authors did not designate a name for the plasmid from which the vga gene was identified from [130].
Table 2. Genetic basis of antibiotic resistance mechanisms in S. aureus.
Antibiotic Class Resistance gene(s), Family or Operon Protein(s) produced Mechanism of Action Gene Location(s) in S. aureus Staphylococcal MGEs References
Aminoglycosides aac Acetyltransferase Antibiotic modification and inactivation Chromosome, plasmid, transposon P: pETBTY825, pSK41, pUR1902, pUR2941

T: IS1181, IS1182, Tn4001, Tn5404, Tn5405 Tn554		 [39][40][41][42][43][44][138][139][140][141][142][143][144][145][146][147][148]
aad, ant Adenylyltransferase
aph Phosphotransferase
β-lactams blaZ β-lactamase Inactivation of β-lactam antibiotics through enzymatic hydrolysis Chromosome, plasmid, transposon P: pETBTY825, pI258, pI9789

T: Tn552		 [58][59][145][149][150][151][152][153][154][155][156][157][158][159]
Cephalosporins,
methicillin		 mecA Penicillin-binding protein 2a (PBP2a) Reduced antibiotic affinity; enables cell wall cross-linking in the presence of β-lactams Chromosome, pathogenicity island (PAI) PAI: SCCmec [149][160][161][162][163][164]
Chloramphenicol cat Chloramphenicol
acetyltransferase		 Enzymatic acetylation of chloramphenicol; antibiotic inactivation Plasmid P: pC194, pC221, pUB112 [165][166][167][168][169][170]
Glycopeptides (e.g., vancomycin) cls Cardiolipin synthase Involved in cell membrane synthesis; increased cls expression led to membrane modification that impaired antibiotic penetration and activity Chromosome - [171][172][173]
mprF Bifunctional membrane enzyme involved in phospholipid synthesis and translocation Increased positive charge of cell membrane and change of membrane fluidity that reduces antibiotic affinity; target modification [174][175][176]
rpoB β-subunit of bacterial RNA polymerase rpoB mutations are frequent in vancomycin-intermediate S. aureus (VISA) strains. They also lead to upregulation of capsule synthesis, attenuated virulence and immune evasion [177][178][179]
walKR (also known as yycFG) Inducible two-component regulator system consisting of a sensor kinase and response regulator Regulation of cell wall synthesis (thickening), biofilm formation, virulence, immune evasion, autolysis [180][181][182][183]
vraS/vraR (vraSR) Stress sensing and regulatory system that overproduces protective enzymes such as penicillin-binding protein 2 (PBP2) and other cell wall biosynthesis genes in response to antibiotic activity [177][184][185][186][187][188]
van operon (e.g., vanA) van operon proteins—refer to Section 2.3. Reduction of antibiotic affinity through cell wall modification Plasmid, transposon P: Inc18-like, pLW1043, pSK41-like

T: Tn1546		 [82][189][190][191][192][193]
Fusidic acid fusA Mutation to the EF-G ribosome complex Antibiotic target modification; reduced antibiotic affinity Chromosome - [194]
fusB FusB protein Prevention of antibiotic interaction with EF-G target site of bacterial ribosome Chromosome, plasmid, transposon P: pUB101

T: IS431/257		 [194][195][196]
fusC FusC protein Chromosome, PAI PAI: SCC476, SCCmecN1, pseudo SCCmec-SCC-SCCCRISPR [194][197][198][199][200][201]
Lincosamides
Oxazolidinones
Phenicols
Pleuromutilins
Streptogramin A		 cfr rRNA methyltransferase Methylation of A2503 bacterial 23S rRNA gene; reduced antibiotic affinity to methylated ribosomes Chromosome, plasmid, transposon P: pSCFS3-like, pSCFS7, pSM19035

T: IS21-558, Tn558		 [202][203][204][205][206][207][208][209][210]
optrAa ABC-F protein Active dislodgement of antibiotics from the ribosomal target site Chromosome, transposon T: Tn6823 [95][99][211]
Linezolid G2576T Point mutation in 23S rRNA gene Ribosomal target modification, reduction of antibiotic affinity Chromosome - [212]
Macrolides
Lincosamides
Streptogramins
(MLS)		 erm Ribosomal methylase Methylation of bacterial 23S rRNA domain V; modification of target site and reduced antibiotic binding affinity Chromosome, plasmid, transposon P: pE194,
pUR1902, pUR2940, pUR2941

T: Tn551, Tn554		 [148][213][214][215][216][217]
lsa Efflux pump Antibiotic efflux Chromosome, plasmid, transposon P: pV7037
T: Tn560		 [110][218][219][220]
mdeA Chromosome - [110][221]
msrA b Plasmid P: pETBTY825, pMS97 [145][222]
Mupirocin mupA Protein modification Target modification; reduced antibiotic affinity Chromosome, plasmid,
transposon		 P: pJ2947, pXU12

T: IS257		 [223][224][225][226][227]
Phosphonic acid (e.g., Fosfomycin) fosB Fosfomycin inactivating enzyme Mn2+-dependent enzymatic modification and inactivation of fosfomycin Chromosome, PAI, plasmid, transposon PAI: SsPI15305

P: pET28, pIP1842

T: IS257-like c		 [117][228][229][230][231][232][233]
Quinolones gyrA, gyrB DNA gyrase mutation Reduced antibiotic binding affinity
Chromosome		 - [213][234]
parC, parE Mutation of topoisomerase IV [213][234]
norA Efflux pump Antibiotic efflux [235]
qnr Pentapeptide repeat protein Protection of DNA gyrase against antibiotic mediated inhibition Plasmid d - [236]
Streptogramin A vat Acetyltransferases Antibiotic modification and inactivation Chromosomally located conjugative elements, plasmid, transposon P: pIP524, pIP680, pIP1156, pIP1714

T: Tn5406		 [126][127][128][129][213][237]
vga Efflux pump Antibiotic efflux Chromosome, plasmid, transposon P: pSA-7,
pVGA, pUR2355, pUR4128, pUR3036, pUR3937

T: Tn5406, Tn5406-like, Tn6133		 [144][237][238][239][240]
Sulfonamides sulA Dihydropteroate synthase Enzymatic overproduction of p-aminobenzoic acid Chromosome - [213]
Tetracyclines tetK, tetL Efflux pump Antibiotic efflux Chromosome, plasmid, transposon P: pT181, pUR1902, pUR2940, pUR2941, pUSA02

T: Tn1545, Tn5801-like (Tn6014), Tn916		 [165][193][241][242][243][244][245][246]
tetM, tetO, tetS e Ribosome protection protein Binding to bacterial ribosome; interference with tetracycline-ribosome binding
Trimethoprim dfrA Dihydrofolate reductase Production of trimethroprim-resistant dihydrofolate reductase Chromosome, plasmid, transposon P: pSK1, pSK639

T: IS257, Tn4003		 [245][247][248][249]
dfrB Reduced antibiotic binding affinity Chromosome - [250][251]
a Confers resistance to oxazolidinones and phenicols only [99][136]. b Confers resistance to macrolides and streptogramins only [137]. c The fosB5 gene was not part of the IS257-like transposon but merely surrounded by two copies of it [231]. d A Nigerian study revealed a very low prevalence of plasmid-mediated qnr genes amongst clinical S. aureus isolates. No plasmid designations were provided from the study [236]. Quinolone resistance is caused primarily in Gram-negative bacteria through chromosomal mutations [252]. e tetS is carried by staphylococci [246] but has not been explicitly found in S. aureus in the literature.
Vancomycin-resistant Enterococcus (VRE) is a frequent cause of clinical outbreaks worldwide [253][254]. An example of this is the VRE clonal sequence type 796 (ST796) which was first detected in 2011 in Australia, then quickly spread both nationwide and internationally to New Zealand [255] before also causing outbreaks in European hospitals beginning in December 2017 [256].

1.2. Staphylococcus aureus

Staphylococcus aureus is a Gram-positive, facultative anaerobic bacterium [257]. Both a commensal as well as a significant pathogen of humans [258], S. aureus is prevalent in community, healthcare [259] and agricultural settings [260][261], asymptomatically colonising up to 30% of the human population [262].
As one of the most versatile and successful opportunistic human pathogens [259][263], S. aureus possesses a large variety of virulence factors [264] that enable host colonisation, tissue damage, immune evasion and progression of disease [264][265]. Consequently, S. aureus infections can be grouped into three general categories: (i) toxinoses such as scalded skin syndrome, food poisoning and toxic shock syndrome; (ii) benign and self-limiting conditions such as superficial skin and soft tissue infections; and (iii) systemic, life-threatening complications such as brain abscesses, meningitis, pneumonia, osteomyelitis, endocarditis, bacteremia, multi-organ failure and sepsis which carry high rates of morbidity and mortality [266][267].
S. aureus infections can be either HA or CA. The characteristics and virulence profiles of CA S. aureus typically differ to those of HA S. aureus [268][269]. HA infections of methicillin-resistant S. aureus (MRSA) were first reported in the 1960s [270], but rarely affected non-hospitalised healthy people and failed to spread efficiently within the community. This was generally attributed to the fitness cost imposed upon HA-MRSA through acquisition of antibiotic resistance elements [271], and is consistent with studies that reported HA-MRSA being generally more drug-resistant [268][272] and have reduced fitness and virulence [273] than CA-MRSA. Nevertheless, HA-MRSA clones remain a major cause of nosocomial infections globally [270].
The global emergence of CA-MRSA [274][275][276][277][278][279] began in the late 1980s [271], and was defined as a MRSA infection in the community whereby the infected persons exhibits no apparent nosocomial risk factors. This suggested that CA-MRSA evolved independently from lineages present in clinical settings. This hypothesis was further supported by the observation that CA-MRSA and HA-MRSA are epidemiologically, clinically, and microbiologically distinct [269][272]. Typically, CA-MRSA differ from HA-MRSA through the former exhibiting low-level susceptibility to non-β-lactam antibiotics, carriage of SCCmec types IV or V and production of Panton-Valentine leukocidins [271]. However, possible transmission between HA-MRSA to CA-MRSA may increase the overlap in similarities between the two MRSA sub-populations [269].
For HA-MRSA, ST239 was traditionally considered to be the dominant global hospital clone [280] and remains prevalent in Asia along with ST5 [281][282]. Elsewhere, the prevalence distribution of HA-MRSA clones will vary depending on geographical location: USA100 (North America) [283][284][285][286], CC5 (Latin America) [287][288], ST22 (United Kingdom), ST225 (central Europe) [282], ST22-IV [2B] (Australia) [289] and ST5 and ST239/241 (Africa) [290].
In the community, the dominant CA-MRSA clone also varies by geographical location: USA300—ST8-IV (North America), USA1100 and USA300-Latin American variant (South America), ST80-IV (Europe), ST93-IV (Australia), high heterogeneity in Asia (no dominant clone) and insufficient data for Africa [291]. Although traditionally considered a HA pathogen, the burden of CA-MRSA disease has been on the rise since its global emergence in the 1990s [292] and it began to appear within HA facilities in the 2000s [271]. Since then, many countries such as Australia [293], China [282], India [294], Kuwait [295], South Korea [296][297] Switzerland [298] United Arab Emirates [299], United Kingdom [300] and the United States [301][302][303] have reported the occurrences of persistence, dissemination, outbreaks and/or outright dominance of CA-MRSA clones within HA facilities which are attributed to the comparatively higher fitness of CA-MRSA through its carriage of smaller SCCmec variants and fewer, if any, other antibiotic resistance determinants [273].
The exact mechanisms driving the divergent evolution of MRSA clones, and reasons for the emergence and replacement or dominance of specific clones in different geographical locations remain unclear [270][274][304][305][306][307]. Researchers hypothesise that factors such as the host population demographics, migration, environmental climate, presence of other microorganism communities (e.g., other bacteria and bacteriophages that can facilitate horizontal gene transfer), spontaneous gene mutations and level of antibiotic use and stewardship are all likely to play contributing roles. With such changing diversity in MRSA clones, rapid and accurate clinical diagnosis, combined with a tailored treatment regimen according to the resistance profile of the clonal type will be essential for effective patient care [291].
S. aureus has demonstrated a remarkable ability to rapidly acquire and develop antibiotic resistance (Figure 2), often achieved through horizontal gene transfer of mobile genetic elements (MGEs) and chromosomal mutations [306]. As a result, an extensive arsenal of resistance mechanisms has emerged in S. aureus that enables resistance to major antibiotic classes typically employed to treat infection (Table 2).
Figure 2. Timeline of antibiotic introduction (above) and subsequent resistance emergence in S. aureus (below) [29][30][33][34][308][309]. Abbreviations: PRSA—Penicillin-resistant S. aureus; MRSA—Methicillin-resistant S. aureus; VISA—Vancomycin-intermediate S. aureus; Q/DRSA—Quinupristin/dalfopristin-resistant S. aureus; LRSA—Linezolid-resistant S. aureus; VRSA—Vancomycin-resistant S. aureus; DRSA—Daptomycin-resistant S. aureus; CRSA—Ceftaroline-resistant S. aureus.
Like enterococci, the rapid emergence of resistance development in S. aureus has been attributed to the misuse and overuse of antibiotics in clinical and agricultural settings [9]. When combined with additional factors such as high rates of asymptomatic colonisation [262][310] and increased accessibility of international travel, S. aureus infections, particularly those caused by antibiotic resistant strains, have reached epidemic proportions in community and clinical settings worldwide [311]. Globally, S. aureus was responsible for more than 250,000 deaths associated with AMR in 2019 [312]. In the United States, S. aureus caused more than 119,000 bloodstream infections which led to nearly 20,000 deaths in 2017 [313]. As with VRE, antibiotic resistant S. aureus has also been designed as a “high priority” and “serious threat” pathogen by the WHO [314] and U.S. CDC [29] respectively.

2. Vancomycin

2.1. Discovery and History

Vancomycin is a tricyclic glycopeptide antibiotic first isolated in 1957 from the fungus Streptomyces orientalis. In vitro experiments showed that it had broad spectrum activity against Gram-positive bacteria, with no detected resistance in staphylococci following serial passages in media containing vancomycin. After showing promising efficacy and safety profiles in animal models, vancomycin (name derived from “vanquish”) entered human clinical trials [33][315]. During an initial clinical trial, vancomycin successfully treated 8 out of 9 patients with severe staphylococcal infection. Therapy failure occurred in one patient who was suffering from empyema, which prevented a therapeutic dose level of vancomycin from being administered [316]. In another human study, 5 out of 6 endocarditis patients who had already experienced antibiotic failure demonstrated resolution of disease indicators; the singular patient who experienced therapy failure had also presented with multiple conditions such as intractable heart failure and shock [317].
The culmination of positive data from these respective clinical trials subsequently resulted in the immediate approval of vancomycin by the U.S. Food and Drug Administration (FDA) in 1958. However, due to perceived nephrotoxicity [33][318][319], vancomycin was originally categorized as a last resort medication reserved for patients who were infected with bacteria that were resistant to frontline drugs or those patients with serious allergies to standard therapy [33]. Today, vancomycin is used as a first-line treatment for MRSA [320][321][322], and remains an important antibiotic used against serious Gram-positive bacterial infections [323][324].

2.2. Mechanism of Action

Vancomycin inhibits the cell wall synthesis of Gram-positive bacteria by binding to D-Ala-D-Ala dipeptide subunits of peptidoglycan monomers anchored to the sugar backbone of alternating N-acetylmuramic acid (MurNac) and N-acetylglucosamine (GlcNac) residues [325][326]. In susceptible bacteria, peptidoglycan monomers normally undergo transglycosylation and transpeptidation by the glycosyltransferase and transpeptidase activities of penicillin-binding proteins (PBPs), forming new peptidoglycan structures through pentaglycine cross-linkage [327][328]. Vancomycin, as a largely hydrophilic molecule, disrupts this process by forming hydrogen bonds to the D-Ala-D-Ala moiety through its aglycon subunit. As a result, this complex leads to a conformational change to the peptidoglycan which prevents subsequent transglycosylase and transpeptidase activity. Consequently, cell wall synthesis is inhibited as new peptidoglycan monomers are unable to be incorporated into the growing peptidoglycan skeleton, eventually leading to bacteriostasis in enterococci [315] or osmotic shock, cell lysis and death in S. aureus (Figure 3) [23][315][329][330].
Figure 3. Mechanism of vancomycin activity. (A) Susceptible bacteria undergo normal cell wall synthesis through enzymatic (transglycosylase and transpeptidase) cross-linking activity in the absence of vancomycin. 1. Bacterial peptidoglycan with unlinked D-Ala-D-Ala monomers. 2. PBP recognises and binds to D-Ala-D-Ala monomers. 3. PBP facilitates the cross-linking of peptidoglycan D-Ala-D-Ala monomers through catalysis of pentaglycine bonds [23][315][325][326][327][328][329]. 4. Newly formed cell wall with complete cross-linking of D-Ala-D-Ala monomers. (B) Vancomycin inhibits peptidoglycan cross-linking in susceptible bacteria through its recognition and binding to D-Ala-D-Ala monomers. 1. Bacterial peptidoglycan with unlinked D-Ala-D-Ala monomers. 2. Vancomycin recognises and binds to D-Ala-D-Ala monomers. 3. Prevention of PBP-mediated catalysis of pentaglycine bonds due to vancomycin’s binding to D-Ala-D-Ala monomers. 4. Peptidoglycan cross-linking is inhibited, disrupting cell wall synthesis which leads to cytostasis (Enterococcus) or cell death (S. aureus) [23][315][325][326][327][328][329]. Created with BioRender.com.
Although adverse effects are still observed from prolonged administration or high concentrations of use, vancomycin’s toxicity has been significantly reduced since its first introduction. This was most likely achieved due to the removal of impurities present in early batches [315]. The improvement in vancomycin’s safety profile, in addition to the emergence of methicillin-resistant bacteria in the 1970s, subsequently lead to its mainstream adoption and use [34]. Today, vancomycin’s utility and importance in modern medicine is highlighted by its inclusion on the WHO’s model list of essential medicines [331].

2.3. Vancomycin Resistance in Enterococcus

The widespread use of vancomycin has predictably resulted in the rapid emergence and spread of vancomycin resistance amongst various Gram-positive bacteria [315]. In 1988, Uttley and colleagues published the first clinical outbreak of highly resistant VRE, with some isolates having minimum inhibitory concentrations (MICs) greater than 2000 µg/mL [332]. Today, the Clinical Laboratory Standards Institute (CLSI) classifies complete vancomycin resistance in Enterococcus with a MIC of ≥32 µg/mL, intermediate resistance as 8–16 µg/mL and susceptible as ≤4 µg/mL using broth microdilution testing [333]. This is consistent with the breakpoints set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) which define the MIC of vancomycin susceptible enterococci to be ≤4 µg/mL and vancomycin-resistant enterococci to be>4 µg/mL [334].
Vancomycin resistance in enterococci is centered around the modification of the vancomycin target site i.e., modification of the D-Ala-D-Ala terminal amino acids of dipeptide monomer subunits into either D-Ala-D-Lac or D-Ala-D-Ser (Figure 4). These mutations confer high- and low-level vancomycin resistant phenotypes respectively. This is because the binding affinity of vancomycin for D-Ala-D-Lac is reduced 1000-fold due to loss of a single hydrogen bond [335] compared to its modestly (6-fold) reduced affinity for D-Ala-D-Ser due to steric hindrance by the D-Ser hydroxyl group [336][337]. As the mechanism of resistance (D-Ala-D-Lac or D-Ala-D-Ser) is determined by different van cassettes, the degree of vancomycin resistance in enterococci will be dependent upon which van operon they express [336]. The different van operons, their respective genes, proteins, and mechanisms of action responsible for these variable resistance levels are summarised in Table 3.
Microorganisms 11 00024 g004 550
Figure 4. Mechanism of high-level vancomycin resistance. 1. Vancomycin-sensitive bacteria expressing D-Ala-D-Ala monomers. 2. Mutated vancomycin-resistant bacteria expressing D-Ala-D-Lac monomers that vancomycin poorly recognises. 3. With D-Ala-D-Lac not bound to vancomycin, PBP can subsequently bind to and catalyse the formation of pentaglycine bonds between MurNac-GlaNac monomers. 4. Bacterial peptidoglycan cross-linking and cell division continue uninhibited.
Table 3. The molecular basis of van-mediated vancomycin resistance in enterococci.
Gene Protein/Function Mechanism of Action References
D-Ala-D-Lac based resistance (VanA-type resistance)—vanA, vanB, vanD, vanF, vanM gene cassettes High level vancomycin resistance
vanA1 Ligase Catalyses the formation of D-Ala-D-Lac depsipeptides [192][338]
vanH Dehydrogenase Catalyses conversion of pyruvate to D-lactate, generating the necessary substrate for D-Ala-D-Lac depsipeptide synthesis [335][339]
vanR/vanS Regulatory System The vanR transcription regulator and the vanS sensor kinase comprise the canonical two-component regulatory system that controls vanHAX expression [340]
vanX Dipeptidase Cleavage of D-Ala-D-Ala into individual D-Ala residues, thus depleting D-Ala-D-Ala dipeptide substrates from the peptidoglycan synthesis pathway; inhibition of D-Ala-D-Ala synthesis and subsequent loss of binding sites for vancomycin [341]
vanY Pentapeptidase D,D-carboxypeptidase activity against D-Ala; reducing availability of D-Ala precursors and therefore favoring the production of peptidoglycan with D-Ala-D-Lac terminals [342][343][344][345][346]
vanZ Unknown Currently unknown; vanZ does not appear to be necessary for vancomycin resistance but is required for resistance to the related glycopeptide teicoplanin [347][348]
D-Ala-D-Ser based resistance (VanC-type resistance)—vanC 2, vanE, vanG, vanL, vanN gene cassettes Low level vancomycin resistance
vanC1 Ligase Synthesis of D-Ala-D-Ser peptidoglycan terminals [336]
vanR/vanS Regulatory system Two-component regulatory system consisting of the VanR transcription regulator and the VanS sensor kinase [336]
vanT3 Membrane-bound serine racemase Catalyses conversion of L-Ser to D-Ser, producing the D-Ser substrates required for D-Ala-D-Ser terminals [349][350][351][352][353][354][355][356][357][358][359]
vanXY3 Bifunctional dipeptidase/pentapeptidase Hydrolyses UDP-MurNac-pentapeptides (D-Ala) and D-Ala-D-Ala [360][361]
1vanA and vanC are the ligase genes of the vanA and vanC operons respectively. Ligase genes are named similarly for the other resistance cassettes e.g., vanB is the ligase gene designation for the vanB operon [336]. 2 The vanC operon is not found in E. faecium or E. faecalis [362]. 3 Not found in D-Ala-D-Lac based vancomycin resistance cassettes [336].
Low-level vancomycin resistance mediated by D-Ala-D-Ser monomers follows the same principle as shown here [335][336][337]. Created with BioRender.com.
High level, D-Ala-D-Lac based vancomycin resistance is encoded by the vanA operon and its homologs vanB, vanD, vanF and vanM. The vanA, vanH, vanX, vanS and vanR genes collectively compose the “core” resistance cassette known as “VanA-type” vancomycin resistance (Figure 5). vanY and vanZ are considered “accessory” genes of the vanA cassette and are not strictly necessary for conferring resistance (Table 3). The naming of homologous genes in all VanA-type operons are identical to each other, with the exception of the ligase gene which is named after its operon i.e., the genes vanA, vanB, vanD, vanF and vanM encode for the ligase proteins in the vanA, vanB, vanD, vanF and vanM operons but the dehydrogenase gene in all five VanA-type resistance operons are named vanH [336]. The vanA genotype is the most common amongst VRE and vancomycin-resistant S. aureus (VRSA) worldwide [362][363].
Figure 5. Molecular mechanisms of vanA-mediated vancomycin resistance. Expression of vanHAX genes are regulated by the two-component vanSR system. D-Ala-D-Ala components are hydrolysed by VanX, with VanY hydrolysing terminal D-Ala-D-Ala residues of existing peptidoglycan precursors not eliminated by VanX. Pyruvate is reduced to D-Lac by VanH, and VanA catalyses the esterification of D-Ala to D-Lac to form vancomycin-resistant peptidoglycan terminal ends. The role of VanZ in mediating vancomycin resistance is unknown and is implicated in teicoplanin resistance only [267][364][365]. Created with BioRender.com.
The D-Ala-D-Ser type resistance encoded by the vanC cassette was discovered in the chromosomes of Enterococcus gallinarum, Enterococcus casseliflavus and Enterococcus flavescens, providing intrinsic, low-level vancomycin resistance [82][362][366][367][368][369][370][371]. Homologs of vanC; vanE, vanG, vanL and vanN were later found in E. faecalis [349][350][372][373], and these operons allow for production of D-Ala-D-Ser peptidoglycan terminals. These cassettes also contain similar genes to those of the VanA-resistance type in addition to two genes exclusive to the D-Ala-D-Ser resistance cassette: a vanT-encoded serine racemase and vanXY-encoded bifunctional dipeptidase/pentapeptidase (Table 3). The naming of homologous genes in VanC-type resistance cassettes follow the same nomenclature as VanA-type resistance operons [336].
The vanA, vanB, vanG, vanM and vanN operons are transferable between bacteria. The distribution of these van operons in enterococci has been reviewed by Ahmed and Baptiste [362]. For a detailed review on the van operons and genes involved in vancomycin resistance, refer to Stogios and Savchenko [336].

2.4. Vancomycin Resistance in S. aureus

In 1996, MRSA which were clinically refractory to vancomycin treatment was reported for the first time in Japan [308]. These strains, named Mu3 and Mu50, had MICs of 3 µg/mL and 8 µg/mL respectively [374] and were later termed hetero-vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) respectively [375]. In 2002, complete VRSA was reported for the first time in the United States [376]. Today, CLSI defines S. aureus complete vancomycin resistance with a MIC of ≥16 µg/mL, intermediate resistance as 4–8 µg/mL and susceptible as ≤2 µg/mL with broth microdilution testing [333]. This is consistent with the breakpoints set by EUCAST which define the MIC of vancomycin susceptible S. aureus to be ≤2 µg/mL and vancomycin-resistant S. aureus to be >2µg/mL [334].
The conversion of vancomycin-susceptible S. aureus (VSSA) to VISA occurs through spontaneous mutations in genes such as walkR, rpoB, vraSR and mprF. Mutations in these genes are thought to confer the wide range of favorable phenotypic changes in VISA that allow for greater vancomycin resistance such as membrane charge modification, upregulation of cell wall biosynthesis genes, cell wall thickening, biofilm formation and modulation of key cellular processes such as immune evasion, virulence attenuation and reduced autolysis (Table 2) [174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][375].
hVISA is defined as the precursor to VISA, and in most cases emerges as a semi-resistant subpopulation of daughter cells from a previously susceptible but heterogenous VSSA population [375]. Following prolonged vancomycin exposure and selection pressure that favors their outgrowth, eventually a homogenous VISA population is achieved [377]. Interestingly, hVISA may also give rise to “slow” VISA (sVISA), a slower growing VISA subpopulation with similar phenotypes to extant “wild type” VISA but with longer doubling times, higher vancomycin MICs (≥6 µg/mL) and VISA phenotype instability (i.e., rapid reversion to hVISA in the absence of drug selection pressure) [375].
Despite the greater therapeutic difficulty in treating VISA infections, VISA appears to be less virulent than VSSA but with a greater ability to colonise and evade the host immune system [378][379]. Prior studies employing a mouse model of skin and soft tissue infection demonstrated that VISA had a much lower invasive capacity than VSSA; VISA also induced lower levels of innate immunity in persistent and chronic infections [379]. Proposed mechanisms for VISA’s virulence reduction include loss-of-activity mutations or dysfunction of the quorum-sensing, virulence regulator system agr [379]. Virulence factors under agr control include expression of the α-hemolysin encoded by hla [380], with mutant or dysfunctional agr VISA isolates found to produce up to 20-fold less α-toxin than VSSA and also less lethal in an in vivo murine bacteraemia model [378]. In addition, VISA had a comparatively higher capacity for biofilm formation than VISA, which are key contributors to S. aureus immune evasion and persistence. This was supported by the upregulation fnbB and sdrCDE genes which are associated with cell adhesion and immune evasion respectively [379].

3. Conclusion

E. faecalis, E. faecium and S. aureus are common human commensal organisms with potential to cause serious, life-threatening infections with exceptional intrinsic and acquired antibiotic resistance capabilities that have increased in prevalence globally in recent decades. This is enabled by the emergence and continued dissemination of mobile van resistance cassettes amongst staphylococci and enterococci through MGEs, which confer high-level vancomycin resistance through modification of the D-Ala-D-Ala peptidoglycan terminal ends in addition to endogenous, non-transferable mutations that give rise to intermediate-level resistance in S. aureus. Although other viable antibiotic combinations are still available for vancomycin resistant infections, novel antibiotics, in addition to alternative non-drug antimicrobial strategies will likely be needed to ensure treatment options remain for increasingly drug-resistant infections in the future.

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Subjects: Microbiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Gen Li
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Mark J. Walker
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David M. P. De Oliveira
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Update Date: 05 Jan 2023
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