Targeted Antibiotic Delivery: Selective Siderophore Conjugation with Daptomycin Confers Potent Activity against Multidrug Resistant <i>Acinetobacter baumannii</i> Both in Vitro and in Vivo

Ghosh, Monisha; Miller, Patricia A.; Möllmann, Ute; Claypool, William D.; Schroeder, Valerie A.; Wolter, William R.; Suckow, Mark A.; Yu, Honglin; Li, Shuang; Huang, Weiqiang; Zajíček, Jaroslav; Miller, Marvin J.

doi:10.1021/acs.jmedchem.7b00102

Cited by 121 publications

(131 citation statements)

References 34 publications

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“…Fimsbactin, an A. baumannii-selective siderophore, was coupled to daptomycin by Ghosh et al, with the hypothesis that coupling of a Gram-negative-targeted siderophore to daptomycin could help transfer daptomycin directly into the cytoplasm, bypassing the need for outer membrane penetration. The resulting conjugate had potent in vivo and in vitro activity against 10 reference A. baumannii strains, including MDR strains (54). For in vivo studies, mice infected with A. baumannii ATCC 17961 were treated with ciprofloxacin, daptomycin, or fimsbactin conjugate.…”

Section: New Therapeutic Optionsmentioning

confidence: 99%

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Isler¹,

Doi

Bonomo

et al. 2019

Antimicrob Agents Chemother

265

179

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Carbapenem-resistantAcinetobacter baumannii(CRAB) is a perilous nosocomial pathogen causing substantial morbidity and mortality. Current treatment options for CRAB are limited and suffer from pharmacokinetic limitations, such as high toxicity and low plasma levels. As a result, CRAB is declared as the top priority pathogen by the World Health Organization for the investment in new drugs. This urgent need for new therapies, in combination with faster FDA approval process, accelerated new drug development and placed several drug candidates in the pipeline. This article reviews available information about the new drugs and other therapeutic options focusing on agents in clinical or late-stage preclinical studies for the treatment of CRAB, and it evaluates their expected benefits and potential shortcomings.

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Section: New Therapeutic Optionsmentioning

confidence: 99%

New Treatment Options against Carbapenem-Resistant Acinetobacter baumannii Infections

Isler¹,

Doi

Bonomo

et al. 2019

Antimicrob Agents Chemother

265

179

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“…Siderophores have also been conjugated with non‐β‐lactam ATBs such as artemisinin (conjugate 24 ) and daptomycin (conjugate 25 ) (Figure ). These non‐β‐lactam synthetic siderophores also showed enhanced ATB activities against Gram‐negative pathogens, and this effect was directly linked to the siderophore transport machinery .…”

Section: Trojan Horse Approaches To Overcome Antimicrobial Resistancementioning

confidence: 99%

“…59 siderophores or siderophore mimics. [78][79][80] Antibiotics from other classes, including ciprofloxacin, 81 spiramycin, 82 vancomycin, 83 norfloxacin, 84,85 and daptomycin 86,87 have also been conjugated with siderophores. Synthetic siderophore-ATB conjugates have been reported to enhance the uptake of the drugs, thus boosting and/or expanding the effectiveness of common ATBs.…”

Section: Siderophore-atb Conjugationsmentioning

confidence: 99%

“…211 The CPP (86) previously demonstrated intrinsic ATB activity against intracellular Salmonella and Brucella bacteria. 212 In Brezden et al's study, kanamycin (85) was linked to (86), with or without a cleavable disulfide linkage, to form the conjugates (87) and (88) (Figure 16). This attachment increased the overall net positive charge of the conjugates (from +8 to +12), therefore, facilitating the penetration and accumulation of the drug into J774A.1 host cells.…”

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confidence: 99%

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Drug delivery systems designed to overcome antimicrobial resistance

Pham

Loupias

Dassonville‐Klimpt

et al. 2019

Medicinal Research Reviews

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Antimicrobial resistance has emerged as a huge challenge to the effective treatment of infectious diseases. Aside from a modest number of novel anti‐infective agents, very few new classes of antibiotics have been successfully developed for therapeutic use. Despite the research efforts of numerous scientists, the fight against antimicrobial (ATB) resistance has been a longstanding continued effort, as pathogens rapidly adapt and evolve through various strategies, to escape the action of ATBs. Among other mechanisms of resistance to antibiotics, the sophisticated envelopes surrounding microbes especially form a major barrier for almost all anti‐infective agents. In addition, the mammalian cell membrane presents another obstacle to the ATBs that target intracellular pathogens. To negotiate these biological membranes, scientists have developed drug delivery systems to help drugs traverse the cell wall; these are called “Trojan horse” strategies. Within these delivery systems, ATB molecules can be conjugated with one of many different types of carriers. These carriers could include any of the following: siderophores, antimicrobial peptides, cell‐penetrating peptides, antibodies, or even nanoparticles. In recent years, the Trojan horse‐inspired delivery systems have been increasingly reported as efficient strategies to expand the arsenal of therapeutic solutions and/or reinforce the effectiveness of conventional ATBs against drug‐resistant microbes, while also minimizing the side effects of these drugs. In this paper, we aim to review and report on the recent progress made in these newly prevalent ATB delivery strategies, within the current context of increasing ATB resistance.

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“…图 14 肠杆菌素、肠杆菌素类似物和基于肠杆菌素的高铁霉素类抗生素 [87] (网络版彩图) Figure 14 Enterobactin, enterobactin analogs β-lactam antibioticsenterobactin conjugates [ 图 16 Fimsbactin、fimsbactin类似物和基于达托霉素的高铁霉素类抗生素 [89] (网络版彩图) Figure 16 Fimsbactin, fimsbactin analogs and fimsbactin-daptomycin conjugate [89] (color online).…”

Section: Figure 13mentioning

confidence: 99%