Designing drugs that overcome antibacterial resistance: where do we stand and what should we do?

Penchovsky, Robert; Traykovska, Martina

doi:10.1517/17460441.2015.1048219

Cited by 66 publications

(54 citation statements)

References 60 publications

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“…Therefore, there is an urgent need to create and employ unconventional strategies for the development of antimicrobial products to tackle the rising of global threats imposed by the spread of antimicrobial resistance [24]. …”

Section: Most Relevant Microbial Threats To Health and Antimicrobimentioning

confidence: 99%

Recent Developments in Antimicrobial Polymers: A Review

et al. 2016

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Antimicrobial polymers represent a very promising class of therapeutics with unique characteristics for fighting microbial infections. As the classic antibiotics exhibit an increasingly low capacity to effectively act on microorganisms, new solutions must be developed. The importance of this class of materials emerged from the uncontrolled use of antibiotics, which led to the advent of multidrug-resistant microbes, being nowadays one of the most serious public health problems. This review presents a critical discussion of the latest developments involving the use of different classes of antimicrobial polymers. The synthesis pathways used to afford macromolecules with antimicrobial properties, as well as the relationship between the structure and performance of these materials are discussed.

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Section: Most Relevant Microbial Threats To Health and Antimicrobimentioning

confidence: 99%

Recent Developments in Antimicrobial Polymers: A Review

et al. 2016

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“…Most importantly, for all new antimalarial entities, the risk of resistance development has to be assessed (Box 1) [34]. The antibacterial field has relied on combination therapy to curb resistance development, particularly in TB [38], and includes combinations of more than 2 partner drugs. This, in theory, would result in targeting different activities in the organism, thereby more effectively curbing the development of resistance against any of the partner components.…”

Section: Continuous Discovery Of Chemically and Mechanistically Novelmentioning

confidence: 99%

“…The antibacterial field further highlights the use of antisense oligonucleotides as a potential means to develop a line of highly adaptable antibiotics [38]. Antisense oligonucleotide (ASO, ~20 bp single-stranded cDNA) binds to their target mRNA, to specifically inhibit gene expression and decreased levels of the target protein [89].…”

Section: Antisense Oligonucleotides (Aso)mentioning

confidence: 99%

“…Antisense antibiotics are amenable to target drug resistance-associated mutations in the target nucleic acid sequence. By utilizing next generation sequencing technology, any mutation caused at DNA or RNA level in response to ASO exposure could easily be determined within hours resulting in adapting the ASO to the new nucleic acid sequence of the resistant target [38] and thus ensuring a quick delivery of new drugs to fight resistant pathogens. At present, two antisense drug have been approved by the U.S. Food and Drug Administration; namely, Formivirsen (Vitravene) as a treatment for cytomegalovirus (CMV) retinitis [90] and Mipomersen (Kynamro) for homozygous familial hypercholesterolemia [91].…”

Section: Antisense Oligonucleotides (Aso)mentioning

confidence: 99%

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Resisting resistance: is there a solution for malaria?

Verlinden

Louw

Birkholtz

2016

Expert Opinion on Drug Discovery

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IntroductionCurrently, widely used antimalarial drugs have a limited clinical lifespan due to parasite resistance development. With resistance continuously rising, antimalarial drug discovery requires strategies to decrease the time of delivering a new antimalarial drug while simultaneously increasing the drug"s therapeutic lifespan. Areas coveredLessons learnt from various chemotherapeutic resistance studies in the fields of antibiotic and cancer research offer potentially useful strategies that can be applied to antimalarial drug discovery. In this review we discuss current strategies to circumvent resistance in malaria and alternatives that could be employed. Expert opinionWe have been "beating back" the malaria parasite with novel drugs for the past 49 years but the constant rise in antimalarial drug resistance is forcing the drug discovery community to explore alternative strategies. Avant-garde anti-resistance strategies from alternative fields may assist our endeavors to manage, control and prevent antimalarial drug resistance to progress beyond beating the resistant parasite back, to stopping it dead in its tracks. Here we investigate the 2 development of strategies that are able to either overwhelm or outwit the parasite in its attempts to develop resistance. Article Highlights box In most instances the malaria parasite develops drug resistance at a faster rate than a novel antimalarial drug can be developed. For antimalarial drug discovery to remain sustainable, the clinical lifespan of an antimalarial drug must as least exceed the time taken to develop the drug. Currently, antimalarial drug resistance is being controlled through the development of novel drugs, which are combined with an appropriate drug partner into a combination therapy. Polypharmacology (multitargeting) may be able to speed up the delivery of a novel antimalarial drug while simultaneously increasing the clinical lifespan of the drug. Unexplored targets such as the virulence potential, hijacked host factors and stress factors may deliver drugs that can effectively resist resistance. Other post-resistance strategies such as molecular decoys and chemogenomics may also prove valuable in curbing resistance.

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“…Due to the rising incidence of antimicrobial resistance in hospitals and the paucity of new therapeutics in the pipeline1 there is renewed interest in innovative approaches such as oligonucleotide therapeutics. Besides the selectivity towards their therapeutic target, there are no known mechanisms by which bacteria could expel oligonucleotides outside their cytoplasm, as they do with small molecule antimicrobials via drug efflux pumps234, as proved, e.g., for the bacterial pathogen Escherichia coli ( E. coli )5.…”

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confidence: 99%

Antimicrobial Nanoplexes meet Model Bacterial Membranes: the key role of Cardiolipin

Marín-Menéndez

Montis

Díaz-Calvo

et al. 2017

Sci Rep

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Antimicrobial resistance to traditional antibiotics is a crucial challenge of medical research. Oligonucleotide therapeutics, such as antisense or Transcription Factor Decoys (TFDs), have the potential to circumvent current resistance mechanisms by acting on novel targets. However, their full translation into clinical application requires efficient delivery strategies and fundamental comprehension of their interaction with target bacterial cells. To address these points, we employed a novel cationic bolaamphiphile that binds TFDs with high affinity to form self-assembled complexes (nanoplexes). Confocal microscopy revealed that nanoplexes efficiently transfect bacterial cells, consistently with biological efficacy on animal models. To understand the factors affecting the delivery process, liposomes with varying compositions, taken as model synthetic bilayers, were challenged with nanoplexes and investigated with Scattering and Fluorescence techniques. Thanks to the combination of results on bacteria and synthetic membrane models we demonstrate for the first time that the prokaryotic-enriched anionic lipid Cardiolipin (CL) plays a key-role in the TFDs delivery to bacteria. Moreover, we can hypothesize an overall TFD delivery mechanism, where bacterial membrane reorganization with permeability increase and release of the TFD from the nanoplexes are the main factors. These results will be of great benefit to boost the development of oligonucleotides-based antimicrobials of superior efficacy.

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Designing drugs that overcome antibacterial resistance: where do we stand and what should we do?

Cited by 66 publications

References 60 publications

Recent Developments in Antimicrobial Polymers: A Review

Recent Developments in Antimicrobial Polymers: A Review

Resisting resistance: is there a solution for malaria?

Antimicrobial Nanoplexes meet Model Bacterial Membranes: the key role of Cardiolipin

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