SUPPLEMENT ARTICLE

Oritavancin: Mechanism of Action

George G. Zhanel,1,2,3,4 Frank Schweizer,1,2 and James A. Karlowsky1,2,3,4
Departments of 1Medical Microbiology, and 2Chemistry, University of Manitoba, and Departments of 3Clinical Microbiology, and 4Medicine, Health
Sciences Centre, Winnipeg, Canada

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Oritavancin is a semisynthetic lipoglycopeptide analogue of vancomycin that contains the heptapeptide
core common to all glycopeptides. It differs from vancomycin by the presence of a hydrophobic
N-4-(4-chlorophenyl)benzyl (also referred to as 4#-chlorobiphenylmethyl) substituent on the disaccharide
sugar, the addition of a 4-epi-vancosamine monosaccharide to the amino acid residue in ring 6, and the
replacement of the vancosamine moiety by 4-epi-vancosamine. One mechanism of action of oritavancin is
inhibition of transglycosylation (important in peptidoglycan synthesis) by binding to D-alanyl-D-alanine stem
termini in Gram-positive bacteria. The inhibition of peptidoglycan synthesis via inhibition of transglycosylation is
common to all glycopeptides (vancomycin) and lipoglycopeptides. Secondary binding of oritavancin to the
pentaglycyl (Asp/Asn) bridging segment in peptidoglycan also occurs, which distinguishes it from vancomycin
and contributes to oritavancin’s activity versus vancomycin-resistant organisms. The presence of the hydrophobic
4#-chlorobiphenylmethyl group allows for interaction and disruption of the cell membrane, resulting in
depolarization, permeabilization, and concentration-dependent, rapid cell death. This mechanism is shared with
telavancin but not vancomycin and results in activity against daptomycin-nonsusceptible organisms. In conclusion,
oritavancin’s mechanism of action involves at least 3 known mechanisms: inhibition of transglycosylation,
inhibition of transpeptidation, and cell membrane interaction/disruption. Oritavancin’s multiple mechanisms of
action confer activity against vancomycin-susceptible and -resistant organisms, as well as rapid, concentration-
dependent killing versus actively growing, stationary phase, and biofilm-producing Gram-positive bacteria.

Reports of multidrug-resistant, Gram-positive patho- problem is the emergence of vancomycin-intermediate

gens such as methicillin-resistant Staphylococcus aureus
(MRSA) appeared in the scientific literature as early as
the 1960s [1, 2]. However, it was not until the 1980s that
MRSA became widespread [1]. The steep rise in the
prevalence of MRSA in hospitals during that decade
resulted in a sharp increase in vancomycin use [1, 2].
Today, healthcare-associated MRSA is a worldwide con-
cern, and the percentage of S. aureus isolates resistant
to methicillin exceeds 60% in some intensive care units
[1, 2]. Many countries, including the United States and
Canada, are also experiencing a significant increase in the
number of community-associated MRSA infections in
otherwise healthy individuals [1, 2]. Compounding the
Correspondence: George G. Zhanel, PhD, MS 673 Microbiology, Health
Sciences Centre, 820 Sherbrook St, Winnipeg, Manitoba R3A 1R9, Canada
(ggzhanel@pcs.mb.ca).
Clinical Infectious Diseases 2012;54(S3):S214–9
Ó The Author 2012. Published by Oxford University Press on behalf of the
Infectious Diseases Society of America. All rights reserved. For Permissions,
please e-mail: journals.permissions@oup.com.
DOI: 10.1093/cid/cir920
S. aureus (VISA), vancomycin-resistant S. aureus (VRSA),
and vancomycin-resistant Enterococcus (VRE), which has
added a greater sense of urgency to the search for novel
antimicrobials with activity against resistant Gram-
positive pathogens [1, 3].
For decades vancomycin was viewed by many as the
gold standard for the treatment of MRSA infections
[4–6]. Although it is active against the vast majority of
MRSA, vancomycin is plagued by poor penetration into
certain tissues (eg, lung) and slow bactericidal activity
[4, 6]. In addition, vancomycin’s minimum inhibitory
concentration (MIC) for Gram-positive pathogens such
as MRSA has been reported to be increasing, with ther-
apeutic failures also being reported [7–11]. Furthermore,
investigators are reporting the development of hetero-
resistant vancomycin-intermediate S. aureus (hVISA) and
VISA [1, 3]. The rampant spread of MRSA and VRE and
the inherent limitations of vancomycin therapy highlight
the need for novel, rapidly bactericidal agents to combat
infections with these pathogens [12].

S214 d CID 2012:54 (Suppl 3) d Zhanel et al

 Eli Lilly identified and developed vancomycin in the 1950s
as a response to the emergence of penicillin-resistant S. aureus
[6, 13, 14]. In the early 1980s, Eli Lilly renewed its efforts to
identify other glycopeptides with enhanced properties relative to
vancomycin (ie, active vs vancomycin-resistant strains, better
pharmacodynamics, etc). They identified chloroeremomycin,
a vancomycin analogue with a different vancosamine sugar than
vancomycin and an additional vancosamine epimer not present
in vancomycin’s structure (Figure 1) [13, 14]. Chloroeremomycin
displayed modestly improved activity compared with vanco-
mycin, against methicillin-susceptible S. aureus (MSSA), MRSA,
and vancomycin-susceptible and -resistant strains of enterococci
[13, 14]. Eli Lilly medicinal chemists synthesized .500 analogues
of chloroeremomycin and identified a chlorobiphenylmethyl
side chain analogue, LY333328 (later known as oritavancin)
[13, 14]. From 1994 to 2001 Eli Lilly, in a screen to gain sub-
stantial anti-VRE activity while maintaining anti-MRSA activity,
developed oritavancin, but terminated its antibacterial discovery/
development program and sold oritavancin to InterMune, Inc, in
2002 [14]. InterMune conducted a variety of clinical trials with
oritavancin but subsequently sold it to Targanta Therapeutics
Corporation (now owned by The Medicines Company) in 2006
[14]. The Medicines Company is continuing to develop orita-
vancin, including performing additional clinical trials.
Oritavancin, a vancomycin analogue, is a semisynthetic
lipoglycopeptide with activity against MRSA, VISA, VRSA,
daptomycin-nonsusceptible S. aureus, and VRE (both VanA
and VanB phenotypes) [3, 5, 13–21]. Oritavancin, which has
novel pharmacokinetics [22, 23], is rapidly bactericidal in
a concentration-dependent manner, and the area under the
concentration–time curve to MIC ratio is the pharmacodynamic
parameter that best describes its activity [5, 15, 24, 25]. This agent
is currently in phase III development as a 1200-mg single dose for
the treatment of acute bacterial skin and skin structure infections,
including those due to MRSA [13, 14, 26, 27]. The purpose of
this report is to review the data available on the mechanisms of
action of oritavancin against Gram-positive pathogens.
Figure 1. Chemical structures of vancomycin, chloroeremomycin, and oritavancin.
STRUCTURE OF ORITAVANCIN
All glycopeptides, including vancomycin, contain a common
heptapeptide core and are glycosylated (Figure 1) [5, 6, 13].
The heptapeptide core contains at least 5 amino acid residues
bearing aromatic side chains (these 5 rings are highlighted in
Figure 1). Oritavancin, a vancomycin analogue, is a synthetic
derivative of the naturally occurring glycopeptide chloroer-
emomycin (Figure 1) [13, 14]. Chloroeremomycin belongs to
the eremomycin class, which differs from vancomycin by the
presence of a 4-epi-vancosamine monosaccharide at the amino
acid residue in ring 6 and the substitution of the vancosamine by
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4-epi-vancosamine (Figure 1) [13, 14]. These structural differ-
ences, compared with vancomycin, confer on chloroeremomycin
an enhanced antimicrobial activity against both vancomycin-
susceptible organisms (through increased affinity for the wild-type
target), as well as improved activity against vancomycin-resistant
organisms [14]. Oritavancin differs from chloroeremomycin by
the addition of a 4#-chlorobiphenylmethyl substituent on the
disaccharide sugar (Figure 1) [13, 14]. This structural alteration
imparts improved activity against vancomycin-susceptible En-
terococcus (VSE) and significantly improved activity against VRE,
including VanA enterococci [13, 28, 29]. The lipophilic side chain
in oritavancin anchors the compound to the cell membrane
through hydrophobic interactions, and it stabilizes the oritavancin
dimer (Figure 2) [15, 29–32]. The formation of dimers is achieved
by interactions involving the disaccharides attached to ring 4 and
the 4-epi-vancosamine on ring 6, as well as the chlorine on ring 2
[13, 32–35]. The dimers formed improve oritavancin’s ability to
bind to its target, including D-alanyl-D-lactate (D-Ala-D-Lac)
present in VanA enterococci [29].
MECHANISM OF ACTION
Peptidoglycan Synthesis Inhibition
The mechanism of action common to all members of the gly-
copeptide class, including vancomycin, is the inhibition of
Oritavancin Mechanism of Action d CID 2012:54 (Suppl 3) d S215
bacterial cell wall synthesis [5, 6]. The cell wall and its major
component, peptidoglycan, are responsible for maintaining cell
shape and structural integrity of the bacterial cell. Peptidoglycan
is a polymer composed of repeating disaccharide-pentapeptide
units, which are synthesized in the cytoplasm. Transport of the
disaccharide-pentapeptide units across the cell membrane oc-
curs in the form of a complex with a lipid carrier (undecaprenyl
pyrophosphate), known as lipid II. Translocation of lipid II
across the cell membrane provides the substrate for trans-
glycosylase enzymes to incorporate the disaccharide-pentapeptide
monomer into the newly synthesized or nascent peptidoglycan.
Vancomycin and other glycopeptides bind to the carboxyl-
terminal acyl-D-alanyl-D-alanine (acyl-D-Ala-D-Ala) residues of
the pentapeptide moiety of lipid II (mechanism 1 in Figure 2)
[13]. This specific binding, which is referred to as the primary
binding site, sterically hinders the transglycosylase enzyme from
incorporating the disaccharide-pentapeptide monomer into na-
scent peptidoglycan. This inhibition of peptidoglycan synthesis by
vancomycin results in a relatively slow (compared with b-lactams)
and concentration-independent bactericidal activity [31].
Like vancomycin, oritavancin has also been reported to inhibit
transglycosylation by binding to the primary site [28, 32, 33]. The
addition of the hydrophobic side chain 4#-chlorobiphenylmethyl
onto the disaccharide sugar confers on oritavancin an increased
binding affinity to the target molecule lipid II (mechanism 1 in
Figure 2. Proposed model depicting vancomycin and oritavancin mechanisms of action. Comparison of the single mechanism of action of vancomycin
(inhibition of transglycosylation—mechanism 1) to the 3 different mechanisms of action of oritavancin (inhibition of transglycosylation—mechanism 1,
inhibition of transpeptidation—mechanism 2, and disruption of bacterial membrane integrity—mechanism 3, depicting oritavancin dimers).
S216 d CID 2012:54 (Suppl 3) d Zhanel et al
Figure 2). Oritavancin’s hydrophobic side chain allows bacterial
cell membrane anchoring, which results in stabilizing the inter-
action with lipid II [32]. The self-association into dimers may
promote cooperative interactions between dimers and adjacent
pentapeptides of the peptidoglycan, which results in increased
binding avidity [13, 15]. Unlike vancomycin, oritavancin is able to
bind to depsipeptides, including D-Ala-D-Lac, which facilitates its
inhibition of cell wall synthesis even in organisms that exhibit
VanA-type resistance [28, 29]. Oritavancin forms homodimers
prior to binding to D-Ala-D-Ala or D-Ala-D-Lac, which increases
its binding affinity for the target site.
Unlike vancomycin, oritavancin has also been reported to
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inhibit transpeptidation by binding to a secondary site (mecha-
nism 2 in Figure 2) [28, 33, 34]. Using solid-state nuclear
magnetic resonance (NMR), the Schaefer group has described
the molecular interactions of oritavancin with the cell wall and
changes in cell wall structure as a result of these interactions
[28, 33, 34]. These studies performed on either S. aureus or
Enterococcus faecium, using metabolic labeling of cell wall
components with amino acids containing NMR-active nuclei,
demonstrated that oritavancin is able to interact with newly
made peptidoglycan components in a more extensive manner
than does vancomycin. Specifically, oritavancin was reported
to bind the peptidic cross-linking portion of the cell wall of
S. aureus (pentaglycine bridge [33, 34]) and of E. faecium (Asx
bridge [28]), in addition to binding the D-Ala-D-Ala termini
of the stem peptide. Thus, oritavancin may retain microbio-
logical activity against vancomycin-resistant organisms (such as
VRE and VRSA, where the termini are modified to D-Ala-D-Lac)
by instead binding the peptide bridge [12, 28, 34]. The addition
of a hydrophobic side chain 4#-chlorobiphenylmethyl on the
disaccharide sugar thus confers on oritavancin increased binding
affinity to lipid II, resulting in inhibition of transglycosylation and
a more pronounced impact on transpeptidation (mechanism 2
in Figure 2), owing to bridge peptide binding. Thus, the si-
multaneous accumulation of D-Ala-D-Ala stems and decrease in
the level of cross-linking is suggestive of an agent acting on both
transglycosylation and transpeptidation [28, 33].
Cell Membrane Alterations
The addition of a hydrophobic side chain 4#-chlorobiphenylmethyl
on the disaccharide sugar confers on oritavancin not only in-
creased binding affinity, which results in inhibition of trans-
glycosylation and transpeptidation, but also cell membrane
anchoring and self-association into dimers, which result in
perturbation of cell membrane integrity in Gram-positive or-
ganisms [13, 29–32, 36]. Studies using the fluorescent probe
3,3#-dipropylthiadicarbocyanine iodide [DiSC3(5)] as an indi-
cator of the degree of depolarization of the plasma membrane
following exposure to drug have shown that challenge with
oritavancin but not vancomycin results in loss of membrane
integrity [15, 31, 32]. The hydrophobic 4#-chlorobiphenylmethyl
side chain of oritavancin was implicated in the mechanism,
resulting in concentration-dependent membrane depolarization
and increased permeability in various resistance phenotypes of
S. aureus and enterococci, which resulted in cell death (VISA,
VRSA, VRE) [15]. Oritavancin interacts with the cell membrane,
facilitating a prime antimicrobial position for peptidoglycan
interactions, disrupting the bacterial membrane potential and
increasing membrane permeability (mechanism 3 in Figure 2)
[15]. Figure 2 compares the single mechanism of action of
vancomycin (inhibition of transglycosylation) to the 3 different
mechanisms of action of oritavancin (inhibition of transgly-
cosylation, inhibition of transpeptidation, and disruption of
bacterial membrane integrity).
Kim et al have recently shown that the hydrophobic 4#-
chlorobiphenylmethyl side chain of oritavancin results in in-
teraction with isolated membrane protoplasts and increases
membrane permeability in artificial liposomes composed of bac-
terial membrane phospholipids [32]. It is important to note that,
although oritavancin’s effects and interactions with the bacterial
cell membrane only occur above a threshold concentration, re-
searchers have concluded that its rapid, concentration-dependent
bactericidal effects against Gram-positive pathogens result from
altering the integrity of the cell membrane [13, 15, 29, 31]. These
findings also argue in favor of the currently studied dosing of
oritavancin in clinical trials for acute bacterial skin and skin
structure infections, that is, single-dose (1200 mg) therapy [27].
Belley et al have recently reported that, unlike vancomycin, or-
itavancin exhibited concentration-dependent bactericidal activity
versus stationary phase inocula of MSSA, MRSA, and VRSA
[29, 31]. As demonstrated for exponentially growing organisms,
oritavancin induced membrane depolorization, increased per-
meability, and resulted in rapid cell death. These investigators
reported a correlation between membrane depolarization and cell
death [15]. Also, unlike vancomycin, oritavancin sterilized bio-
films of MSSA, MRSA, and VRSA at minimal biofilm eradication
concentrations (MBECs) of between 0.5 and 8 lg/mL [31]. The
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bactericidal potency of oritavancin was evident as the MBECs
were within 1 dilution of the respective MIC performed with
planktonic cells [31]. The authors hypothesized that the hydro-
phobic 4#-chlorobiphenylmethyl side chain of oritavancin dis-
rupts membrane potential and increases membrane permeability
in Gram-positive pathogens. It is the concentration-dependent
oritavancin-induced cell membrane perturbation and resulting
permeability that results in cell death.
Ultrastructural Changes
The ultrastructural effects of oritavancin and vancomycin on
MRSA and VRE were examined using transmission electron
microcroscopy [29]. Both vancomycin-exposed (exposure at
16 lg/mL for 3 hours) and oritavancin-exposed (exposure at
1 lg/mL for 10 minutes) MRSA demonstrated cell wall thick-
ening and membrane inclusions, whereas only oritavancin-
exposed cells demonstrated deformed septa that were thickened
and misshapen with loss of staining intensity of nascent septal
cross walls. In VRE, oritavancin exposure (0.12 lg/mL or
1 lg/mL for 10 minutes) induced formation of large mem-
brane inclusions and septal distortions. The authors hypoth-
esized that oritavancin-induced septal defects may be due to
membrane disruption because of oritavancin’s ability to di-
merize and form cooperative interactions [29]. It is clear that in
both MRSA and VRE, oritavancin demonstrates pronounced
effects on cell division that are not observed with vancomycin.
This is likely an indication that oritavancin is able to target
critical yet vulnerable sites to achieve rapid concentration-
dependent bactericidal activity.
MECHANISM OF RESISTANCE
Even though oritavancin demonstrates activity against clinical
isolates of VanA, VanB, and VanC enterococci, it has been
demonstrated in vitro using agar-based methods that moderate
decreases in susceptibility level resistance to oritavancin can
occur in enterococci isolates exhibiting the VanA or VanB
phenotype [37]. However, resistance in isolates that harbor the
vanB operon was only observed when the operon was altered
Oritavancin Mechanism of Action d CID 2012:54 (Suppl 3) d S217
such that it became inducible by teicoplanin or constitutively
expressed [37]. Isolates that produce peptidoglycan precursors
terminating in D-Lac may exhibit reduced susceptibility to or-
itavancin if all precursors terminating in D-Ala are eliminated
[37]. This has been achieved in vitro by increasing resistance
gene expression or reducing D-Ala-D-Ala production [37]. Such
changes resulted in a maximum 16-fold increase in oritavancin
MIC compared with the parent strain [37]. The expression of
the vanZ gene of the vanA gene cluster also resulted in a 4-fold
increase in MIC through an unknown mechanism [37].
Limited data are available regarding the selection of
oritavancin-resistant mutants in the laboratory. This is likely
because, in agar assays, oritavancin diffuses slowly and binds to
agar, which makes interpretation of experiments to investigate
single-step resistance selection difficult [38]. Bozdogan et al
[38], studying a vancomycin-resistant S. aureus that was serially
selected using vancomycin, showed a 32- to 64-fold increase in
vancomycin MIC, a 16- to 128-fold increase in teicoplanin
MIC, and a 16- to 64-fold increase in dalbavancin MIC, but only
a 2- to 4-fold increase in oritavancin MIC. Thus far, it has not
been possible to select for high-level oritavancin resistance in
the laboratory, and there have been no instances of decreased
oritavancin susceptibility emerging during or after oritavancin
therapy in clinical studies to date [5, 13, 27]. Whether this is due
to the fact that oritavancin demonstrates multiple different
mechanisms of action is unknown.
CONCLUSIONS
Oritavancin’s mechanism of action involves at least 3 known
mechanisms: inhibition of transglycosylation, inhibition of
transpeptidation, and cell membrane interaction/disruption.
Oritavancin’s multiple mechanisms of action confer activity
against vancomycin-susceptible and -resistant organisms as
well as rapid, concentration-dependent killing versus acti-
vely growing, stationary phase, and biofilm-producing Gram-
positive bacteria.
Notes
Supplement sponsorship. This article was published as part of a sup-
plement entitled ‘‘Oritavancin for the Treatment of Serious Gram-Positive
Infections,’’ sponsored by The Medicines Company.
Potential conflicts of interest. G. Z. received funding from The
Medicines Company. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed in the Acknowledgements
section.
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