Synthetic Antimicrobial Peptidomimetics with Therapeutic Potential

Haug, Bengt Erik; Stensen, Wenche; Kalaaji, Manar; Rekdal, Øystein; Svendsen, John S.

doi:10.1021/jm701600a

Cited by 148 publications

(150 citation statements)

References 48 publications

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…1). As a result, this peptide is active against Staphylococcus epidermidis, a welldescribed biofilm producer associated with device-related infections (20,29). Similar Arg-X-Arg molecules were created during research of protease susceptibility; the most active derivative contained a bulky para-phenyl naphthalene (PPN) substitution as the variable component (69).…”

Section: Increasing Activitymentioning

confidence: 99%

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Findlay

Zhanel

Schweizer

2010

Antimicrob Agents Chemother

264

208

View full text Add to dashboard Cite

2Naturally occurring cationic antimicrobial peptides (AMPs) and their mimics form a diverse class of antibacterial agents currently validated in preclinical and clinical settings for the treatment of infections caused by antimicrobial-resistant bacteria. Numerous studies with linear, cyclic, and diastereomeric AMPs have strongly supported the hypothesis that their physicochemical properties, rather than any specific amino acid sequence, are responsible for their microbiological activities. It is generally believed that the amphiphilic topology is essential for insertion into and disruption of the cytoplasmic membrane. In particular, the ability to rapidly kill bacteria and the relative difficulty with which bacteria develop resistance make AMPs and their mimics attractive targets for drug development. However, the therapeutic use of naturally occurring AMPs is hampered by the high manufacturing costs, poor pharmacokinetic properties, and low bacteriological efficacy in animal models. In order to overcome these problems, a variety of novel and structurally diverse cationic amphiphiles that mimic the amphiphilic topology of AMPs have recently appeared. Many of these compounds exhibit superior pharmacokinetic properties and reduced in vitro toxicity while retaining potent antibacterial activity against resistant and nonresistant bacteria. In summary, cationic amphiphiles promise to provide a new and rich source of diverse antibacterial lead structures in the years to come.The rise in antibiotic resistance among pathogenic bacteria and the declining rate of novel drug discovery are common concerns in medicine (66), driving research into new antibacterial classes and novel drugs in order to maintain the existing ability to treat infectious diseases, especially those caused by multidrug-resistant (MDR) organisms (49, 51).While the enzymatic inhibitors from which many of our strongest antibiotics are derived are highly effective in the microbial world, higher-order organisms do not appear to rely entirely on such selective inhibitors (27). These organisms instead produce a number of broad-range antimicrobial peptides (AMPs), which do not target any single molecule or process but instead associate with cellular membranes, resulting in depolarization, lysis, and cell death through a disruption of the membrane topology. A subset of these peptides is able to translocate into the cell and disrupt cellular processes, such as protein and DNA synthesis (33). AMPs play a key role in the human immune system, and mutations affecting their production and expression have been linked to diseases such as morbus Kostmann and Crohn's disease (56, 75).Membrane targeting offers advantages over standard methods of drug design and antibiotic activity due to the wide variety of active structures and a reduced development of resistance mechanisms (78). Nevertheless, potential cytotoxicity to the host cells remains a major unsolved challenge (43). Mutants resistant to AMPs have been developed in the laboratory (54); however, such mutants may ...

show abstract

Section: Increasing Activitymentioning

confidence: 99%

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Findlay

Zhanel

Schweizer

2010

Antimicrob Agents Chemother

264

208

View full text Add to dashboard Cite

show abstract

“…LTX-109 (Lytixar; Lytix Biopharma AS, Oslo, Norway) is one such novel SAMP which rapidly kills bacteria via membrane disruption and has not been associated with cross-resistance to other available drugs. LTX-109 has also been shown to have a low propensity for the development of resistance (5,6,8).…”

mentioning

confidence: 99%

In Vitro Activities of LTX-109, a Synthetic Antimicrobial Peptide, against Methicillin-Resistant, Vancomycin-Intermediate, Vancomycin-Resistant, Daptomycin-Nonsusceptible, and Linezolid-Nonsusceptible Staphylococcus aureus

Saravolatz

Pawlak

Johnson

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

“…The mechanism of action of LTX-109 represents a new and innovative bactericidal approach via a direct membrane disruption (17,18). The product has been shown not to be affected by cross-resistance to other available drugs and has demonstrated a low propensity for development of resistance (17,18,24). In the present study, a significant reduction of S. aureus CFU was demonstrated already after 2 days, although bacterial recurrence was observed in all but one subject 5 days after the end of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…LTX-109 is a broad-spectrum, fast-acting bactericidal antimicrobial drug that binds to negatively charged membrane components on the bacterial cell, which is followed by membrane disruption and cell lysis (17,18). Nonclinical and clinical studies have demonstrated that topical application of LTX-109 (1 to 5%) has a good safety profile and a low bioavailability (19).…”

mentioning

confidence: 99%

LTX-109 Is a Novel Agent for Nasal Decolonization of Methicillin-Resistant and -Sensitive Staphylococcus aureus

Nilsson

Janson

Wold

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Nasal decolonization has a proven effect on the prevention of severe Staphylococcus aureus infections and the control of methicillin-resistant S. aureus (MRSA). However, rising rates of resistance to antibiotics highlight the need for new substances for nasal decolonization. LTX-109 is a broad-spectrum, fast-acting bactericidal antimicrobial drug for topical treatment, which causes membrane disruption and cell lysis. This mechanism of action is not associated with cross-resistance and has a low propensity for development of resistance. In the present study, persistent nasal MRSA and methicillin-sensitive S. aureus (MSSA) carriers were treated for 3 days with vehicle or with 1%, 2%, or 5% LTX-109. A significant effect on nasal decolonization was observed already after 2 days of LTX-109 treatment in subjects treated with 2% or 5% LTX-109 compared to vehicle (P < 0.0012 by Dunnett=s test). No safety issues were noted during the 9-week follow-up period. Minimal reversible epithelial lesions were observed in the nasal cavity. The systemic exposure was very low, with a maximum concentration of drug in plasma (C max ) at 1 to 2 h postdosing (3.72 to 11.7 ng/ml). One week after treatment initiation, LTX-109 was not detectable in any subject. Intranasal treatment of S. aureus with LTX-109 is safe and reduces the bacterial load already after a single day of treatment. Hence, LTX-109 has potential as a new and effective antimicrobial agent with a low propensity of resistance development that can prevent infections by MSSA/MRSA during hospitalization. (This study has been registered at ClinicalTrials.gov under registration no. NCT01158235.) N asal carriage of Staphylococcus aureus is considered a marker of extended skin carriage and colonization by S. aureus. The colonization is often asymptomatic, but most severe S. aureus infections are caused by endogenous strains from the patient (1-5).Persistent nasal colonization by S. aureus, including methicillin-resistant S. aureus (MRSA) strains, has shown to be a major risk factor for surgical-site (6) and renal dialysis (5, 7) infections. Such individuals have a substantially increased risk for S. aureus hospital-acquired infections (8), with up to as many as 11 to 22% of methicillin-sensitive and -resistant S. aureus carriers developing nosocomial infections during hospital admission (9). In addition, patients carrying S. aureus can be a source of transmission to noncarriers, which subsequently can lead to health care-related exogenous infections.The spread of S. aureus remains unquestionably a serious challenge in infection control in hospitals, and in an attempt to reduce the S. aureus infection rates, prevention programs aiming at decolonizing individual nasal S. aureus carriers have been implemented. The most well-established regimen recommended in several national guidelines (e.g., in the 1998 United Kingdom guideline and the upcoming U.S. CDC guideline) is using a combination of 5 to 7 days of treatment with nasal mupirocin ointment and chlorhexidine soap (4,5,(10)(11)(12...

show abstract

Synthetic Antimicrobial Peptidomimetics with Therapeutic Potential

Cited by 148 publications

References 48 publications

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

Cationic Amphiphiles, a New Generation of Antimicrobials Inspired by the Natural Antimicrobial Peptide Scaffold

In Vitro Activities of LTX-109, a Synthetic Antimicrobial Peptide, against Methicillin-Resistant, Vancomycin-Intermediate, Vancomycin-Resistant, Daptomycin-Nonsusceptible, and Linezolid-Nonsusceptible Staphylococcus aureus

LTX-109 Is a Novel Agent for Nasal Decolonization of Methicillin-Resistant and -Sensitive Staphylococcus aureus

Contact Info

Product

Resources

About