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http://www.microbiologia.unige.it/dpb/indexxx.htmDinamica delle Popolazioni BattericheLaboratorio di Microbiologia Sperimentale ed

Epidemiologia

Nuovi bersagliSintesi acidi grassi(fab, fatty acid biosynthesis)PDF, peptidil deformilasiSintesi acidi teicoici (WTA,wall teicoic acid)Sintesi lipopolisaccaride, LpxCInibizione riboswitchSubunita DNA girasi (topoisomerasi II)(ATPasi)Ossidazione Inibizione pompa efflussoCell division (Fts)Metalli pesanti


Epidemiologia

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


Epidemiologia


Inibitori del metabolismo degli acidi grassi (Fab)

AFN 1252 (API-1252) inibisce una reduttasi che catalizza una reazione essenziale per il metabolismo degli ac. grassiAFN-1252 ha uno spettro d’attività molto limitato S. aureus ma non altri Gram-positivi o Gram-negativi.


Epidemiologia

MUT056399.

AFN-1252;



Epidemiologia

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


Epidemiologia


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


Epidemiologia

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.



Epidemiologia

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.


Epidemiologia

Nuovi bersagli (LPS)


Epidemiologia

Nuovi bersagli (LPS)

ACHN-971 inibisce la sintesi di LPS nei Gram-

negativi inclusoP. aeruginosa e altri

Gram-negativi(manca clinica)


Epidemiologia

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.


Epidemiologia


Epidemiologia

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.


Epidemiologia

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


Epidemiologia

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)


Epidemiologia


Cyclothialidine (Ro 09-1437) GR122222X has been considered as a promising inhibitor whose

modifications might lead to more potent compounds against the

enzyme.


Epidemiologia

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


Epidemiologia


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


Epidemiologia

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.


Epidemiologia


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


Epidemiologia

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.


Epidemiologia



Epidemiologia

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.


Epidemiologia

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.


Epidemiologia

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.


Epidemiologia


Epidemiologia

The resistance nodulation division protein RND


Epidemiologia


Epidemiologia

The Efflux Inhibitor Phenylalanine-Arginine -Naphthylamide (PAN) Permeabilizes the Outer

Membrane of Gram-Negative Bacteria

The membrane permeabilizing activity of PAN 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 PAN 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.


Epidemiologia

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


Epidemiologia

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.


Epidemiologia

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


Epidemiologia

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

Antibacterial mechanisms of metal toxicity

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