In situ potentiometric method to evaluate bacterial outer membrane-permeabilizing ability of drugs: Example using antiprotozoal diamidines

Ando, Makoto; Kamei, Rie; Komagoe, Keiko; Inoue, Tsuyoshi; Yamada, Keiichi; Katsu, Takashi

doi:10.1016/j.mimet.2012.09.033

Cited by 9 publications

(9 citation statements)

References 23 publications

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“…It was shown to potentiate the activity of typical Gram-positive-only drugs against Gram-negative bacteria in vitro and in a systemic Acinetobacter baumannii mouse infection model. Importantly, this activity was retained in colistin-resistant strains. , Since pentamidine has already been in clinical use for the treatment of trypanosomiasis, leishmaniasis, and babesiosis since 1937, its safety and side effects have been extensively assessed. Recent efforts have yielded lipophilic vancomycin analogues that were able to permeabilize both the inner and outer membrane of Gram-negative bacteria while retaining their ability to inhibit peptidoglycan activity …”

Section: Part 2: Antibiotic Combinationsmentioning

confidence: 99%

Multitarget Approaches against Multiresistant Superbugs

2020

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Despite efforts to develop new antibiotics, antibacterial resistance still develops too fast for drug discovery to keep pace. Often, resistance against a new drug develops even before it reaches the market. This continued resistance crisis has demonstrated that resistance to antibiotics with single protein targets develops too rapidly to be sustainable. Most successful long-established antibiotics target more than one molecule or possess targets, which are encoded by multiple genes. This realization has motivated a change in antibiotic development toward drug candidates with multiple targets. Some mechanisms of action presuppose multiple targets or at least multiple effects, such as targeting the cytoplasmic membrane or the carrier molecule bactoprenol phosphate and are therefore particularly promising. Moreover, combination therapy approaches are being developed to break antibiotic resistance or to sensitize bacteria to antibiotic action. In this Review, we provide an overview of antibacterial multitarget approaches and the mechanisms behind them.

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Section: Part 2: Antibiotic Combinationsmentioning

confidence: 99%

Multitarget Approaches against Multiresistant Superbugs

2020

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“…These observations indicated that DB745 could potentially interfere in the formation/metabolism of membranous structures within these parasites. In this context it is interesting to note that a recent study by Ando et al (2012) demonstrated that treatment with related compounds such as diminazene, pentamidine and 4′6′-diamidino-2-phenylindole (DAPI) increased the permeability of bacterial outer membranes.…”

Section: Efficacy and Selectivity Of Amidines And Their Derivatives Amentioning

confidence: 99%

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

et al. 2013

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SUMMARY Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

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“…Importantly, exposure of wild type E. coli to various combinations of pentamidine and rifampicin only generated mutants that displayed resistance to rifampicin (frequency of spontaneous resistance to rifampicin 4.2×10 −8 ; observed frequency of spontaneous resistance to pentamidine < 8.3×10 −10 ; Supplementary Table 6), suggesting that pentamidine may maintain clinical efficacy without the rapid development of resistance. Interestingly, the whole-cell antibacterial activity of pentamidine has been recognized for upwards of 70 years in the context of both Gram-positive 19,24 and Gram-negative 19,25,26 bacteria, however this molecule has yet to be pursued as a modern clinical therapy, presumably due to insufficient potency in vitro . Indeed, with conventional knowledge suggesting that the concentrations of pentamidine required for activity in vitro are beyond those that are clinically achievable in humans, there have been no compelling data to suggest that pentamidine would display therapeutic efficacy in vivo .…”

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confidence: 99%

Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance

et al. 2017

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The increasing use of polymyxins1 in addition to the dissemination of plasmid-borne colistin resistance threatens to cause a serious breach in our last line of defense against multidrug resistant Gram-negative pathogens, and heralds the emergence of truly pan-resistant infections. Colistin resistance often arises through covalent modification of lipid A with cationic residues such as phosphoethanolamine (PEtN) – as is mediated by Mcr-12 – which reduce the affinity of polymyxins for lipopolysaccharide (LPS)3. Thus, new strategies are needed to address the rapidly diminishing number of treatment options for Gram-negative infections4. The difficulty in eradicating Gram-negative bacteria is largely due to a highly impermeable outer membrane, which serves as a barrier to many otherwise effective antibiotics5. Here, we describe an unconventional screening platform designed to enrich for non-lethal, outer membrane-active compounds with potential as adjuvants for conventional antibiotics. This approach identified the antiprotozoal drug pentamidine6 as an effective perturbant of the Gram-negative outer membrane through its interaction with LPS. Pentamidine displayed synergy with antibiotics typically restricted to Gram-positive bacteria, yielding effective drug combinations with activity against a wide range of Gram-negative pathogens in vitro, and against systemic Acinetobacter baumannii infections in mice. Notably, the adjuvant activity of pentamidine persisted in polymyxin resistant bacteria in vitro and in vivo. Overall, pentamidine and structural analogs represent unexploited molecules for the treatment of Gram-negative infections, particularly those having acquired polymyxin resistance determinants.

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In situ potentiometric method to evaluate bacterial outer membrane-permeabilizing ability of drugs: Example using antiprotozoal diamidines

Cited by 9 publications

References 23 publications

Multitarget Approaches against Multiresistant Superbugs

Multitarget Approaches against Multiresistant Superbugs

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance

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