Addressing the global need to combat multidrug resistance: carbohydrates may hold the key
2014; Future Science Ltd; Volume: 6; Issue: 14 Linguagem: Inglês
10.4155/fmc.14.109
ISSN1756-8927
Autores Tópico(s)Antimicrobial Peptides and Activities
ResumoFuture Medicinal ChemistryVol. 6, No. 14 EditorialFree AccessAddressing the global need to combat multidrug resistance: carbohydrates may hold the keyQifang Wang & Chang-Chun LingQifang WangAlberta Glycomics Center & Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary Alberta, T2N 1N4, Canada & Chang-Chun LingAlberta Glycomics Center & Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary Alberta, T2N 1N4, CanadaPublished Online:4 Nov 2014https://doi.org/10.4155/fmc.14.109AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: anti-adhesion therapyantibioticscarbohydratedrug resistanceinhibitorsvaccineFigure 1. Examples of some monovalent and multivalent anti-adhesive compounds based on d-mannopyranosides used to inhibit FimHlectin.Figure 2. Chemically synthesized conjugate vaccine related to PS-II antigen of hypervirulent Clostridium difficile ribotype 027.Antimicrobial resistance has become a formidable challenge of our time, threatening the health of the global population [1]. The most recent report by the WHO confirmed that this threat is "no longer a prediction for the future", but a development "happening right now in every region of the world". Although the overuse and misuse of antibiotics have been accounted as the primary cause for the development of multidrug resistance, it should be realized that our general antibacterial strategy should bear the principal blame as this approach primarily relies on the use of antibiotics that are aiming to either kill bacteria or inhibit their growth [2]. During recent years, many important roles that gut bacteria play in human physiology have been gradually appreciated [3]; together, they are believed to contribute substantially to the continual health as well as pathophysiology of the host such as interacting with host immune systems, assisting the host in digestion and the absorption of nutrients and secreting important metabolites capable of affecting key physiological processes of the host. Unfortunately, a drastic alternation of host bacterial populations by external influences such as the treatment by antibiotics could have an unintended impact on the microbiota, as the bactericidal agent could wipe out significant populations of drug-sensitive strains of bacteria, resulting in diverse short-term and potentially long-term effects on host health and physiological conditions. Most seriously, if drug-resistant mutants survive the treatment, they are presented with an environment of altered microbiota and therefore opportunities to flourish; ultimately, they could turn into dominant pathogens, preventing the re-establishment of a healthy microbiota. The drug-resistant genes of enriched bacterial strains could also be horizontally transferred to other species eventually, causing the other strains in the microbiota to become drug resistant. The unmetabolized antibiotics can be excreted as active agent into the environment, creating other ecological problems. Thus the generation of multidrug-resistant super-pathogens is directly linked to our current antibacterial strategy which unintentionally promotes drug resistance. Unfortunately, most antibiotics currently available for prescriptions show broad-spectrum activities thus are incapable of differentiating bad bacteria from good ones. Therefore, the administration of such nonselective agents will unavoidably result in significant 'collateral damage' to the microbiota, leading to complications such as recurring secondary infections and such problems are extremely difficult to treat. The most well known is the Clostridium difficile associated diarrhea, which accounts for approximately 336,000 cases annually in the USA alone [4].It is clear to us that future antibacterial developments should aim at therapeutics capable of preserving diversity of microbiota while targeting specifically the disease-causing pathogen. They do not necessarily need to be bacteriocidal, but need to be able to interrupt a key step during the infectious process. For example, selectively inhibit the growth of a particular group of pathogenic organisms or clear it from the host. Designing such ideal anti-infective agents requires the in-depth understanding and knowledge of molecular mechanisms involved in infection caused by different strains of microorganisms. Vaccination should be another area of focus. This approach has been very effective at preventing infectious diseases and has contributed to the eradication of some of the most deadly pathogens. In the new era where multidrug-resistant bacteria widely spread, vaccination appears to be a promising solution to the issue because of the specificity and efficacy of the approach. It is true that vaccination is not effective when applied to people already infected with a pathogen, but pre-immunizing populations with antigens of eminent strains of drug-resistant bacteria will allow people to gain lasting immunity to the pathogen. It is encouraging that so far no vaccine-resistant strains have been reported. The development of targeted delivery technologies for anti-infectives should be a third area of research focus. The most desired delivering systems should be the ones that actively target a particular strain of bacteria by recognizing specific molecular structures expressed on the surface of the pathogen or exploiting a unique metabolic pathway of the microorganism.Combating multidrug resistance with carbohydratesCarbohydrates, a group of complex natural products, are well known to be primary sources of nutrients for bacteria and other pathogens. They are also deeply involved in a variety of fundamental biological processes of bacteria. For example, they are main constituents found in two families of important natural polymers: the lipopolysaccharides (produced by Gram-negative bacteria) [5] and capsular polysaccharides (expressed by Gram-positive bacteria) [6]. These surface polymers have immense structural diversities that are very specific to bacterial strains and they play diverse roles in bacterial ecology and physiology. Carbohydrates are also one class of compounds implicated in one of the key steps during an infection by mediating specific interactions between bacterial fimbrial lectins (adhesins) and host tissues. Moreover, many bacterial toxins also bind to specific glycoconjugates of host. Thus carbohydrates play a spectrum of vital roles in the survival and growth of bacteria as well as in their infectious process cycle. For the purpose of designing new vaccines and new anti-infectives with the required high specificity and targeting capability, carbohydrate-based analogs and mimetics may hold the keys in future medicinal chemistry against drug-resistant bacteria, as any of the key biological pathways that bacteria depend on for their growth, adhesion, colonization and invasion could constitute a potential target.Carbohydrate-based anti-adhesive agentsA significant body of research work has been carried out during the last decade to use synthetic carbohydrates in anti-adhesion therapies to inhibit bacterial fimbrial lectins [7,8]. This approach has been regarded as very safe to clear infection without promoting drug resistance. Host recognition and adhesion is a universal mechanism and a prerequisite for a successful infection. To avoid being removed from the host by the body's mechanical and natural cleansing mechanism, the bacteria express specific protein receptors, which appear at the tip of their fimbriae (or pili) to bind to specific carbohydrate sequences on the host. A variety of complex carbohydrate structures that have been recognized by different bacterial lectins was reviewed by Sharon et al. [9,10]. Synthetic analogs of recognized carbohydrates could potentially act as competitive inhibitors to block the binding, thus, the colonization of pathogenic bacteria on host is prevented; this allows the body's natural clearance to clear out the pathogens. In principle, this antibacterial approach has the potential to be very specific, as it only acts on those bacteria that show binding specificity to the used carbohydrate structure and thus does not alter the microbiota in a major way. Most importantly, it does not attempt to kill bacteria, thus will not affect bacterial viability, therefore, there is no selection pressure on the bacteria. In principle, random mutation could still generate bacteria resistant to the anti-adhesion therapies, but the mutation also affects the bacteria's ability to colonize on host at the first place. Consequently, these bacterial mutants are naturally selected against. Despite the promise that anti-adhesion therapies could bring, the research into the development of carbohydrate-based anti-adhesive agents is still at its infancy.The uropathogenic Escherichia coli has been the main bacterial system studied so far. The bacteria cause urinary tract infections (UTIs) which affect a large portion of the world population resulting in significant morbidity. UTIs also account for high medical costs. Uropathogenic E. coli expresses type 1 fimbriae, which is equipped with the FimH lectin (FimH) that shows specificity to d-mannose. Based on solved crystal structure of FimH [11], numerous monovalent and multivalent d-mannose derivatives have been synthesized to study their binding with FimH (Figure 1) and a few of them show nanomolar inhibitory activity to FimH (1A–D) [12–15]. The biphenyl derivative (1B) was reported to be 2,000,000-times more potent than d-mannose and is orally bioavailable. The indolinylphenyl α-d-mannopyranoside (1C) was recently reported [14] to be the most potent anti-adhesion drug candidate for treatment of UTIs on a mouse model. When the compound was administered at the low dosage of approximately 1 mg/kg (∼25 μg/mouse), the minimal therapeutic concentration was maintained for more than 8 h to prevent UTIs. Impressively, in a treatment study, the same compound could reduce the colony-forming units in the mouse bladder by almost four orders of magnitude, comparable to the standard antibiotic treatment with ciprofloxacin (8 mg/kg). Multivalent inhibitors such as the glycocluster (2) bearing three d-mannose units have been reported in the literature [16].Another class of carbohydrates that shows anti-adhesive functions concerns human milk oligosaccharides (HMOs). Their natural functions are to provide nutrition to the infants. During recent years, they have been the subject of increasing studies because they are believed to have a range of other biological activities [17] such as acting as prebiotics by providing nutrients to gut microbiota and also preventing the adherence of pathogenic bacteria to intestines in infants. Many HMOs have structures similar to carbohydrates displayed on the epithelial cells, thus they likely act as anti-adhesive agents; this could be exploited to use them to combat drug-resistant bacteria. However, one challenge is to manufacture HMOs in large scales.Carbohydrate-based vaccinesThe development of carbohydrate-based conjugate vaccines to prevent infections has been a hot research topic for a long time in carbohydrate chemistry [18–22], because of the availability of a rich repertoire of targets based on bacterial polysaccharide structures. Recently, focus has shifted to eminent multidrug-resistant strains [23]. For example, Seeberger et al. have reported [24] the total chemical synthesis of a conjugate vaccine (Figure 2) based on the repeating hexasaccharide found in the capsular polysaccharides (PS-II) of C. difficile. The synthesized hexasaccharide was conjugated to an immunogenic protein (CRM197) and the authors successfully raised carbohydrate-specific IgG antibodies. In addition, conjugate vaccines related to C. difficile capsular polysaccharide (PS-I) have also been succeeded recently by two research groups [25,26]. Obtaining semi-synthetic conjugate vaccines should also be possible using purified bacterial polysaccharides.Targeting carbohydrate-binding bacterial toxinsTo increase the success of an infection, many pathogenic bacteria express a class of extracellular proteins called toxins that can damage host via different mechanisms. For example, some of them act as enzymes to interrupt key signal pathways of host cells and some others kill host cells by forming 'leaky' pores on the cell membranes. To gain access to host cells, bacterial toxins are capable of binding to carbohydrates displayed on host cells. Neutralizing bacterial toxins using carbohydrate-based inhibitors has been an extensively studied area in carbohydrate chemistry during recent years; substantial progress has been achieved [27–29]. Some synthetic efforts have also been dedicated to neutralize toxins expressed by multidrug-resistant pathogens like C. difficile [30,31].Today we have gained considerable understanding on established mutualism between bacteria and human hosts. The development of future antibacterial strategies should evolve based on new knowledge in order to yield the greatest success. While eliminating pathogenic microorganisms will still be the goal in developing future anti-infectives, preserving the overall health of a functional microbiota and minimizing the risk of promoting drug resistance should be part of the consideration. In light of the speculated 'postantibiotic' era looming on the horizon, carbohydrates may hold the keys in the development of next generations of antibacterial medicines, because of their involvement in many aspects of bacterial growth, development and pathogenicity. The structural complexities of involved carbohydrates define the characteristics of different host–bacterial interactions. Undoubtedly, synthetic analogs of carbohydrates and glycomimetics capable of interfering with those interactions will be attractive targets to be studied for becoming novel anti-infectives with much desired selectivity.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. 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(Cambridge) 47(45), 12397–12399 (2011).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByStructural diversity and biological importance of ABO, H, Lewis and secretor histo-blood group carbohydratesRevista Brasileira de Hematologia e Hemoterapia, Vol. 38, No. 4 Vol. 6, No. 14 Follow us on social media for the latest updates Metrics History Published online 4 November 2014 Published in print September 2014 Information© Future Science LtdKeywordsanti-adhesion therapyantibioticscarbohydratedrug resistanceinhibitorsvaccineFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.No writing assistance was utilized in the production of this manuscript.PDF download
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