From genes to sequences to antibiotics: prospects for future developments from microbial genomics

Kotra, Lakshmi P.; Vakulenko, Sergei B.; Mobashery, Shahriar

doi:10.1016/s1286-4579(00)00360-9

Cited by 13 publications

(6 citation statements)

References 75 publications

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“…Whereas the search for novel targets for antibiotics from the genomic information is ongoing (6,115,152,195,237), no antibacterial agent based on these efforts has so far entered clinical trials. Meanwhile, structural knowledge of the ribosome, the target for aminoglycosides, has invigorated the field of antibiotic development.…”

Section: Discussionmentioning

confidence: 99%

Versatility of Aminoglycosides and Prospects for Their Future

2003

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Aminoglycoside antibiotics have had a major impact on our ability to treat bacterial infections for the past half century. Whereas the interest in these versatile antibiotics continues to be high, their clinical utility has been compromised by widespread instances of resistance. The multitude of mechanisms of resistance is disconcerting but also illuminates how nature can manifest resistance when bacteria are confronted by antibiotics. This article reviews the most recent knowledge about the mechanisms of aminoglycoside action and the mechanisms of resistance to these antibiotics

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Section: Discussionmentioning

confidence: 99%

Versatility of Aminoglycosides and Prospects for Their Future

2003

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“…New antibiotics are traditionally selected for their activity against pathogen‐specific proteins. This conventional approach is aimed at minimizing the risk of developing a lead compound that will display activity toward host proteins 1–8. A corollary to this is the general consideration that any attempt to target homologous proteins between the host and pathogen should be avoided due to toxicity concerns.…”

Section: Introductionmentioning

confidence: 99%

Indel‐based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor‐1α

et al. 2007

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We propose a novel strategy for selective targeting of essential pathogen proteins that contain sizable indels (insertions/deletions) in their sequences compared with their host orthologues. This approach has been tested on elongation factor-1alpha (EF-1alpha) from the protozoan pathogen Leishmania donovani. Leishmania EF-1alpha is 82% identical to the corresponding human orthologue, but possesses a 12 aminoacid sequence deletion compared with human EF-1alpha. We used this indel-differentiated region to design small molecules that selectively bind to leishmania EF-1alpha and not to the human protein. Three unrelated molecules were identified with the capacity to inhibit protein synthesis in leishmania by up to 75% while exhibiting no effect on human protein translation. These candidates may serve as prototypes for future development of antiprotozoan therapeutics. More generally, these findings provide a basis for a novel drug design platform. This platform targets essential pathogen proteins that are highly conserved across species, and consequently would not typically be considered to be conventional drug targets. We anticipate that such indel-directed targeting of essential proteins in microbial pathogens may help address the growing problem of antibiotic resistance.

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“…One of the major problems is the localization of the drug target and an efficient drug delivery that can hardly be analyzed by omics tools (124). Therefore requirement of drug response databases -databases that deposit pharmacokinetic and pharmacodynamic data-are also gaining prominence.…”

Section: Resultsmentioning

confidence: 99%

Designing Novel Antibacterials: Application of Omics Science

Zaman¹,

Razzaque²

2014

Klimik Dergisi

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ÖzetAntibiyotikler, zararlı bakteriyel patojenleri yok ederek ya da inaktif hale getirerek etki gösteren ajanlardır. Günümüzde antibiyotiklerin tasarlanmasında genom bilimi, proteom bilimi, metabolom bilimi ve interaktom bilimi gibi "om" bilimlerinden (ya da "omik" bilimlerden) büyük ölçüde yararlanılmaktadır. Bu derlemede bu bilimlerin basitten karmaşığa giden farklı yönle-ri tartışılmaktadır. Piramidin en altındaki basit dizi analizinden üst kısmındaki karmaşık -yapısal, fonksiyonel ve interaksiyonelanalizlerin tümü, omik bilimlerin kapsamına girmektedir. Dizi karşılaştırması, bakterilerdeki ilaç direncine ilişkin yeni bilgiler sunabilmesi nedeniyle, yeni antibiyotik geliştirilmesinde son derece önemlidir. Öte yandan, konak proteininin dizilenmesi, etkili antibiyotiklerin sentetik olarak üretilmesine olanak tanıyabilir. Günümüzde bilgisayar destekli bağlanma teknikleri kullanıldığı yapıya dayalı molekül tasarımı, ilaç tasarım süreçlerinde geniş ölçüde kabul gören rutin bir işlem haline gelmiştir. Ayrıca, mikroçip ekspresyonu, protein-protein etkileşimli essey yöntemle-riyle elde edilen yeni ve yüksek verimli veriler, çok daha fazla ilaç hedefinin keşfi için yeni ufuklar açmaktadır. Konak-patojen etkileşimini sistemler düzeyinde anlamak için gösterilen yoğun çabalar, tüberküloza ve benzer pek çok karmaşık hastalığa kar-şı etkili antibiyotiklerin tasarlanması sürecini hızlandırmıştır. Özetle, bu derlemede omik bilimlerin, yeni antibiyotiklerin keşfi alanındaki paradigmayı, gittikçe artan bir biçimde nasıl değiş-tirdiğine ilişkin çeşitli örnekler sunulmaktadır. Omik yaklaşım, önümüzdeki dönemde bu süreci daha da hızlandıracak ve antibiyotiklerin maliyetini daha da düşürecektir. AbstractAntibacterials are agents that act against pernicious bacterial pathogens by killing or inactivating them. At present, designing antibacterials have been assisted greatly by omics sciences-genomics, proteomics, metabolomics and interactomics. This review discusses different aspects of the omics sciences in simple to complex hierarchies. From the simplest of sequence analysis to more complex on the pyramid -structural, functional and interactional analysis-all comprises the grand ambit of omics science. Sequence comparison can reveal novel information about drug resistance in the bacteria and thus can be of momentous significance for designing improved antibacterials. On the other hand, sequence characterization of the host protein can lead to production of effective antibiotic synthetically. Nowadays, structure based molecular designing, using computational docking techniques, has become a widely accepted routine work in drug designing processes. Moreover, new high-throughput data from microarray expression, protein-protein interaction assay are opening up a new vista for detecting more and more drug targets. Extensive focus put on to understand host-pathogen interaction on systems level has greatly accelerated the process of designing effective antibacterials against tuberculosis and many such complex diseases. Summarizing, this ...

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From genes to sequences to antibiotics: prospects for future developments from microbial genomics

Cited by 13 publications

References 75 publications

Versatility of Aminoglycosides and Prospects for Their Future

Versatility of Aminoglycosides and Prospects for Their Future

Indel‐based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor‐1α

Designing Novel Antibacterials: Application of Omics Science

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