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 d’attività
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 targocilresistant 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)
Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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Nuovi bersagli (LPS)
ACHN-971 inibisce la
sintesi di LPS nei Gramnegativi incluso
P. aeruginosa e altri Gramnegativi(manca clinica)
Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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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 broadspectrum 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 Gramnegative bacteria.
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Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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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 Gramnegative bacteria, including E. coli and P. aeruginosa, with no
preexisting clinical resistance. ACHN-975 has completed a
phase 1 doubleblind, randomized, placebo-controlled, singleascending-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 gyrase–DNA 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).
Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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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.
Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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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-resistant
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 2aminobenzimidazole as biofilm inhibitor, and VRT-752586 with great
activity against gram-negative bacteria, the dual target suggests that
spontaneous mutation toward resistance is rare
(<5.2×10−10).
This compound is active against FQ-R bacteria
Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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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 dall’acido
barbiturico e inibisce le topoisomerasi
con un meccanismo diverso dai FQ.
Possiede un ampio spettro d’attività
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 Grampositive 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 4°C for 1 year and at 20°C 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 drugresistant 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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Dinamica delle Popolazioni Batteriche
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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Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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The resistance nodulation division protein RND
Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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Laboratorio di Microbiologia Sperimentale ed Epidemiologia
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The Efflux Inhibitor Phenylalanine-Arginine bNaphthylamide (PAbN) Permeabilizes the Outer
Membrane 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 Gramnegative pathogens due to an inability to breach the
outer membrane barrier.
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Dinamica delle Popolazioni Batteriche
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, δ-aminolevulinic acid dehydratase; FbaA,
fructose-1,6-bisphosphate aldolase; NQR,
NADH:quinone oxidoreductase; PDF, peptide
deformylase; PvdS, a σ-factor (σ24) 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.
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Dinamica delle Popolazioni Batteriche