nuovi bersagli - universitÀ degli studi 14anuov.pdf · laboratorio di microbiologia sperimentale...

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Dinamica delle Popolazioni Batteriche Laboratorio di Microbiologia Sperimentale ed Epidemiologia

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



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




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.



MUT056399.

AFN-1252;




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




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



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.




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.



Nuovi bersagli (LPS)



Nuovi bersagli (LPS) ACHN-971 inibisce la

sintesi di LPS nei Gram-negativi incluso

P. aeruginosa e altri Gram-negativi(manca clinica)



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.



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.



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



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).

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.



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




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

(<5.2×10−10).

This compound is active against FQ-R bacteria




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.




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



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.



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 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.



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.



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.



The resistance nodulation division protein RND



The Efflux Inhibitor Phenylalanine-Arginine b- Naphthylamide (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 Gram-negative pathogens due to an inability to breach the

outer membrane barrier.



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.

Metal-based compounds antimicrobial agents



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.



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.

Antibacterial mechanisms of metal toxicity



d | Some can interfere with nutrient assimilation. e | They can also be genotoxic.

Antibacterial mechanisms of metal toxicity

nuovi bersagli - universitÀ degli studi 14anuov.pdf · laboratorio di microbiologia sperimentale...

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