Nuovi bersagli

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Nuovi bersagli

• Sintesi acidi grassi(fab, fatty acid
  biosynthesis)
• PDF, peptidil deformilasi
• Sintesi acidi teicoici (WTA,wall teicoic acid)
• Sintesi lipopolisaccaride, LpxC
• Inibizione riboswitch
• Subunita b DNA girasi (topoisomerasi II)(ATPasi)
• Ossidazione
• Inibizione pompa efflusso
• Cell division (Fts)
• Metalli pesanti

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Nuovi bersagli (Fab)

• The FabI inhibitor MUT056399 has potent
  antistaphylococcal activity. It was shown to be
  specific for inhibition of FabI in S. aureus and
  E. coli but did not inhibit the FabK homologs
  from other Gram-positive bacteria. While the
  frequency of resistance selection in vitro was
  low, it resulted in two S. aureus populations of
  FabI mutants, leading to low and high resistance
  (MICs of 0.5 to 4 g/ml and 32 g/ml,
  respectively). In 2010, results from a phase 1
  ascending-dose study in healthy human volunteers
  indicated an elimination half-life of
  approximately 1 h

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Nuovi bersagli (Fab)

• Inibitori del metabolismo degli acidi grassi
  (Fab)
• AFN 1252 (API-1252) inibisce una reduttasi che
  catalizza una reazione essenziale per il
  metabolismo degli ac. grassi
• AFN-1252 ha uno spettro dattività molto limitato
  S. aureus ma non altri Gram-positivi o
  Gram-negativi.

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Nuovi bersagli (Fab)
AFN-1252
MUT056399.
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Nuovi bersagli (PDF)

• Peptide deformylase (PDF), a metalloprotease that
  removes the N-formyl group present in all newly
  synthesized bacterial polypeptides, plays an
  essential role in protein maturation and is a
  highly conserved broad-spectrum target. PDF
  inhibitors therefore represent a new type of
  antibacterial agent with a novel mode of action
  and provide an alternative for the treatment of
  hospitalized patients with CAP and SSSIs caused
  by pathogens resistant to current therapies. The
  design of PDF inhibitors for potential clinical
  use has been the subject of research in a number
  of laboratories over the past decade, partly
  inspired by the discovery that actinonin, a
  naturally occurring antibacterial agent, is an
  inhibitor of PDF

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Nuovi bersagli (PDF)

• LBM415 (PDF-713) inibitore della sintesi proteica
  peptidedeformylase(PDF)
• Attivo su Gram-positivi e Haemophilus influenzae.
  
• Attivo su S.aureus ma facilmente evolve verso la
  resistenza

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Nuovi bersagli (PDF)
GSK1322322 is a novel PDF inhibitor of the
hydrazide class, has shown good safety and
pharmacokinetic properties. GSK1322322 is
currently being developed for the oral and
intravenous treatment of acute bacterial skin
and skin structure infections (SSSI) and
hospitalized patients with CAP. The spectrum of
activity of GSK1322322 includes a collection of
H. influenzae, M. catarrhalis, S. pneumoniae, S.
aureus, and S. pyogenes strains.
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Nuovi bersagli (WTA)
The compound showed antimicrobial activity
against S. aureus with an MIC value of 0.3 µM,
which is 12 times as strong as the parent
compound. Also, targocil is active against MRSA
with the same potency. The in vivo study
indicated that targocil caused no adverse effects
with a dose of 75 mg/kg in a mouse model.
Furthermore, target analysis with
targocil-resistant mutants confirmed that
targocil shares the same target TarG as 1835F03.
In current, targocil is evaluated in pre-clinical
trial for treatment of MRSA infections.
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Nuovi bersagli (LPS)
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Nuovi bersagli (LPS)

• ACHN-971 inibisce la sintesi di LPS nei
  Gram-negativi incluso
• P. aeruginosa e altri Gram-negativi(manca clinica)

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Nuovi bersagli (LPS)

• The zinc-dependent metalloamidase
  UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine
  deacetylase (LpxC), catalyzes the committed step
  of lipid A (endotoxin) biosynthesis. LpxC is an
  essential, single copy gene that is conserved in
  virtually all Gram-negative bacteria.
• Many potent LpxC inhibitors have been identified,
  and most contain a hydroxamate group targeting
  the catalytic zinc ion. Although early
  LpxC-inhibitors were either narrow-spectrum
  antibiotics or broad-spectrum in vitro LpxC
  inhibitors with limited antibiotic properties,
  CHIR-090 is a powerful antibiotic that controls
  the growth of E. coli and P. aeruginosa, with an
  efficacy rivaling that of the FDA-approved
  antibiotic ciprofloxacin. CHIR-090 inhibits a
  wide range of LpxC.
• The success of CHIR-090 suggests that potent
  LpxC-targeting antibiotics may be developed to
  control a broad range of Gram-negative bacteria.

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Nuovi bersagli (LPS)

• Achaogen is developing novel antibiotics that
  inhibit outer membrane biosynthesis via a
  previously unexploited target, LpxC. ACHN- 975
  represents a first-in-class agent with a novel
  mechanism of action with good antibacterial
  activity (MIC of 1 g/ml) against a broad spectrum
  of MDR Gram-negative bacteria, including E. coli
  and P. aeruginosa, with no preexisting clinical
  resistance. ACHN-975 has completed a phase 1
  doubleblind, randomized, placebo-controlled,
  single-ascending-dose study to assess safety,
  tolerability, and PK and recently terminated a
  phase 1 multiple-dose study.

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Nuovi bersagli (riboswitch)

• BRX-1555 inibisce riboswitches.
• Riboswitches controllano le sintesi batteriche
  regolando la produzione di mRNA.
• Sono presenti in Gram-positivi e Gram-negativi
  BRX-1555 è il primo di questi inibitori mostra
  potente attività su C. difficile

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Nuovi bersagli (ATPase)
Bacterial DNA gyrase is a well-established target
with commercial success, exemplified by
quinolones such as ciprofloxacin (1a). However,
resistance is now a problem for this class of
antibacterials in addition to most other classes.
Gyrase consists of two heterodimeric subunits,
GyrA and GyrB. The quinolone class of molecules
inhibits GyrA and induces cell death by trapping
the gyraseDNA complex, inducing oxidative
damage, and preventing DNA replication. Compounds
like novobiocin (1b) inhibit GyrB, which blocks
ATPase activity, thus depriving the source of
energy needed for DNA replication. GyrB as a
target offers an opportunity such as a lack of
cross-resistance to the quinolones. Some other
known GyrB inhibitors are the cyclothialidines
(represented by 1c) and pyrrolamides (1d). In
addition the aminobenzimidazoles (1e) and the
pyrazolthiazole class of GyrB inhibitors (Fig. 1).
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Nuovi bersagli (ATPase)

• Cyclothialidine (Ro 09-1437) GR122222X has been
  considered as a promising inhibitor whose
  modifications might lead to more potent compounds
  against the enzyme.

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Nuovi bersagli (ATPase)
Pyrrolamides show a potent in vitro activity
against selected Gram-positive and Gram-negative
pathogens, including meticillin-resistant
Staphylococcus aureus, meticillin- and
quinolone-resistant S. aureus, vancomycin-resistan
t enterococci, penicillin-resistant Streptococcus
pneumoniae and -lactamase-producing Haemophilus
influenzae and Moraxella catarrhalis. They
demonstrated bactericidal activity, with
frequencies of spontaneous resistance 1 10-7.
The antibacterial activity, spectrum and mode of
action of these compounds suggest that they will
be candidates for the treatment of several
clinical indications, including respiratory and
soft tissue infections. A pyrrolamide derivative
also showed activity against Mycobaterium.
tuberculosis
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Nuovi bersagli (ATPase)

• A novel aminobenzimidazole class of
  antimicrobials has recently been developed. They
  are low molecular weight, potent dual inhibitors
  of the bacterial DNA gyrase and topoisomerase IV
  enzymes that target the GyrB and ParE subunits,
  which translates into a potent antimicrobial
  activity against both Gram-positive and some
  Gram-negative bacterial species.
• Some studies indicate a good activity of this
  compound (VT12-008911) against Neisseria
  gonnorrhoeae, a N-1 substituted
  2-aminobenzimidazole as biofilm inhibitor, and
  VRT-752586 with great activity against
  gram-negative bacteria, the dual target suggests
  that spontaneous mutation toward resistance is
  rare
• (lt5.210-10).
• This compound is active against FQ-R bacteria

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Nuovi bersagli (ATPase)

• The pyrazolothiazole class evolved to a class of
  GyrB inhibitors with potent enzyme and moderate
  antibacterial activity. They possess activity
  against S. aureus and S. pneumoniae, but appear
  to be actively effluxed from E. coli. Perhaps the
  most interesting observation to arise from a
  study is the ability of the carbamate analogs to
  act as selective inhibitors of E. coli GyrB over
  S. aureus GyrB. Structural studies explain this
  selectivity by defining the differences of the
  binding site created by Ile-51, Leu-103, and
  Ile-175 in S. aureus GyrB compared to E. coli
  where the isoleucines are valines and Leu-103 is
  a methionine.

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Nuovi bersagli (ATPase)

• QPT-1 è un inibitore delle topoisomerasi
  batteriche. Deriva dallacido barbiturico e
  inibisce le topoisomerasi con un meccanismo
  diverso dai FQ.
• Possiede un ampio spettro dattività
  antibatterica incluso MDR e non presenta
  tossicità per le cellule eucariotiche

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Nuovi bersagli (ATPase)

• This novel compound (kibdelomycin), produced by
  Kibdelosporangium sp, is a potent inhibitor of
  bacterial type-II topoisomerases, preferentially
  inhibiting the ATPase activity of DNA gyrase and
  topoisomerase IV. It has broad spectrum activity
  against Gram-positive bacteria such as
  Staphylococcus aureus (MRSA), Streptococcus
  pneumoniae, Enterococcus faecalis, and Bacillus
  subtilis, and also is active against the
  Gram-negative Haemophilus influenzae. It is the
  first potent inhibitor of bacterial type-II
  topoisomerases discovered in the last 60 years,
  and does not show cross-resistance with other
  gyrase inhibitors. Its mechanism of action is
  similar but not identical to that of other gyrase
  inhibitors, such as the coumarin antibiotics
  novobiocin and coumermycin A1 and the
  fluoroquinoline antibacterial ciprofloxacin.
  However, kibdelomycin is active against
  novobiocin-resistant and coumermycin-resistant
  strains of S. aureus. It is also active against
  the S. aureus strain that is resistant to
  ciprofloxacin.

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Nuovi bersagli (ATPase)
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Nuovi bersagli (ossidanti)

• N-Chlorotaurine (ClHN-CH2-CH2-SO3H) is an
  endogenous mild oxidant belonging to the class of
  active chlorine compounds (chloramines) with
  broad-spectrum microbicidal activity against
  Gram-positive and Gram-negative bacteria,
  viruses, fungi (yeasts and molds), protozoa, and
  worm larvae. It can be synthesized chemically as
  a sodium salt (ClHN-CH2-CH2-SO3Na, abbreviated
  NCT), which is very well water soluble and can be
  stored at 4C for 1 year and at 20C for 3 weeks
  with a loss of activity of approximately 10. In
  clinical trials, NCT at a concentration of 1 (55
  mM) has been shown to be very well tolerated and
  effective at different body sites, such as the
  eye, the outer ear, skin ulcerations, the urinary
  tract, and other body cavities. There is an unmet
  medical need for safe and effective CVC lock
  solutions for the prevention of both catheter
  blockage and infection.

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Nuovi bersagli (Fts)

• PC190723 is representative of a new class of
  potent small-molecule antibacterial compounds
  that kill bacterial cells by inhibiting the
  essential protein FtsZ. In addition to their
  therapeutic potential, PC190723 and analogs may
  also be useful reagents for further studies on
  the biology of FtsZ and bacterial cell division.
  The potency of PC190723 against drug-resistant S.
  aureus, its efficacy in in vivo models of
  infection, and its structural and physicochemical
  properties make it an excellent candidate for
  optimization into a therapy to treat
  staphylococcal infection.

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Nuovi bersagli (efflusso)

• The phenolic diterpene totarol (MP-601205) had
  good antimicrobial activity against effluxing
  strains of S. aureus. Subinhibitory
  concentrations reduced MICs of selected
  antibiotics suggesting that it may also be an
  efflux pump inhibitor (EPI). A totarol-resistant
  mutant that overexpressed norA was created to
  separate antimicrobial from efflux inhibitory
  activity. Totarol reduced ethidium efflux from
  this strain by 50 at 15µM (¼ MIC) and
  combination studies revealed marked reductions
  in ethidium MICs. These data suggest that totarol
  is a NorA EPI as well as an antistaphylococcal
  antimicrobial agent.

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The resistance nodulation division protein RND
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The Efflux Inhibitor Phenylalanine-Arginine
b-Naphthylamide (PAbN) Permeabilizes the
OuterMembrane of Gram-Negative Bacteria

• The membrane permeabilizing activity of PAbN
  could be considered an asset, as it would promote
  its own entry into the cells where it can access
  its efflux pump targets. Small molecules such as
  PAbN that increase outer membrane permeability
  and/or impair drug efflux have excellent
  potential as antibiotic adjuvants that can reduce
  the effective doses of current drugs. They may
  also expand the range of usable antibiotics to
  those that so far have limited effectiveness
  against Gram-negative pathogens due to an
  inability to breach the outer membrane barrier.

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Metal-based compounds antimicrobial agents
Metals have been used as antimicrobial agents
since antiquity, but throughout most of history
their modes of action have remained unclear.
Recent studies indicate that different metals
cause discrete and distinct types of injuries to
microbial cells as a result of oxidative stress,
protein dysfunction or membrane damage. The
design of metal-based compounds for use as
antimicrobial agents and alternatives to
antibiotics.  Silver has been used as an
antimicrobial since antiquity, yet its mechanism
of action remains unclear. Silver disrupts
multiple bacterial cellular processes, including
disulfide bond formation, metabolism, and iron
homeostasis. These changes lead to increased
production of reactive oxygen species and
increased membrane permeability of Gram-negative
bacteria that can potentiate the activity of a
broad range of antibiotics against Gram-negative
bacteria in different metabolic states, as well
as restore antibiotic susceptibility to a
resistant bacterial strain.
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Antibacterial mechanisms of metal toxicity. a
Metals can lead to protein dysfunction. ALAD,
d-aminolevulinic acid dehydratase FbaA,
fructose-1,6-bisphosphate aldolase NQR,
NADHquinone oxidoreductase PDF, peptide
deformylase PvdS, a s-factor (s24) from
Pseudomonas aeruginosa.
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Antibacterial mechanisms of metal toxicity
b They can also lead to the production of
reactive oxygen species (ROS) and depletion of
antioxidants. c Certain metals have been shown
to impair membrane function.
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Antibacterial mechanisms of metal toxicity
d Some can interfere with nutrient
assimilation. e They can also be genotoxic.