Back to the future: antibody-based strategies for the treatment of infectious diseases

Before antibiotics, sera from immune animals and humans were used to treat a variety of infectious diseases, often with successful results. After the discovery of antimicrobial agents, serum therapy for bacterial infections was rapidly forsaken. In the last two decades, problems with treatment of newly emerged, reemerged, or persistent infectious diseases necessitated researchers to develop new and/or improved antibody-based therapeutic approaches. This article reviews some information on the use of antibodies for the treatment of infectious diseases, with special reference to the most seminal discoveries and current advances as well as available treatment approaches in this field.     

Will genomics revolutionize antimicrobial drug discovery?

Utilizing genome sequence data from bacterial and fungal pathogens for the discovery of new antimicrobial agents has received considerable attention, both practical and critical, from the pharmaceutical and biotechnological communities. Although no new drugs derived from genomics-based discovery have been reported to be in a development pipeline, the utilization of genomics has revolutionized many aspects of drug discovery. The application, utility, opportunity, and challenges afforded by many of these new approaches are discussed.     

Antimicrobial dyes and mechanosensitive channels

The search for new and effective antimicrobial agents has never been as important; however, since the discovery of antibiotics, exploring the antimicrobial activity of dyes has been forgotten. Antimicrobial dyes are an untapped resource and have the ability to potentially combat the spread of drug-resistant bacteria either alone or as antimicrobial adjuvants. The mechanosensitive ion channel of large conductance (MscL) is highly conserved and ubiquitous in bacterial species. There is evidence to suggest that at least one triphenylmethane dye acts through the highly conserved MscL channel and combining the two approaches of exploring the mechanism of action of other triphenylmethane dyes or antimicrobial dyes in general and the novel MscL target provides a new opportunity for further exploration.     

Immunomodulators as an antimicrobial tool

The spectrum of infectious diseases has shifted in the past 50 years to include those caused by microbes that cause disease predominantly in immunocompromised individuals. This phenomenon has underscored the dependence of microbial virulence on the immune status of the host. The limited efficacy of the available antimicrobial armamentarium in immunocompromised individuals, combined with increasing resistance to these agents, has led to an urgent need for new therapies for infectious diseases. Immunomodulation represents a novel approach to antimicrobial therapy that depends on bolstering host immunity, rather than direct antimicrobial activity. Immunomodulators can be divided into those that are specific to pathogens (pathogen-specific) and those that are not specific to pathogens (non-specific). However, to date only a few immunomodulators have been evaluated for their efficacy as antimicrobial tools.     

Imidazo[4,5-<Emphasis Type="Italic">a</Emphasis>]quinindolines as highly effective antibacterial agents

Resistance to antimicrobial agents is a concern that exists globally and has a considerable impact on human and animal health, so that the discovery of new antibacterial compounds has become increasingly more important in combating infectious disease. In this paper, imidazo[4,5-a]quinindolines are introduced as new antibacterial agents against Gram-positive and Gram-negative bacteria. These pentacyclic compounds are synthesized by the reaction of N-alkyl-5-nitrobenzimidazoles with 2-(1-alkyl-1H-3-indolyl)acetonitrile under basic conditions in excellent yields. The structures of newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectral data. The antibacterial activities of the synthesized compounds were screened against standard strains of two Gram-positive and two Gram-negative bacteria using the broth microdilution method. Most of the compounds studied showed promising activities against both types of bacteria.     

Bactericidal,quorum quenching and anti-biofilm nanofactories: a new niche for nanotechnologists

Despite several conventional potent antibacterial therapies, bacterial infections pose a significant threat to human health because they are emerging as the leading cause of death worldwide. Due to the development of antibiotic resistance in bacteria, there is a pressing demand to discover novel approaches for developing more effective therapies to treat multidrug-resistant bacterial strains and biofilm-associated infections. Therefore, attention has been especially devoted to a new and emerging branch of science “nanotechnology” to design non-conventional antimicrobial chemotherapies. A range of nanomaterials and nano-sized carriers for conventional antimicrobial agents have fully justified their potential to combat bacterial diseases by reducing cell viability, by attenuating quorum sensing, and by inhibiting/or eradicating biofilms. This communication summarizes emerging nano-antimicrobial therapies in treating bacterial infections, particularly using antibacterial, quorum quenching, and anti-biofilm nanomaterials as new approaches to tackle the current challenges in combating infectious diseases.     

Resistance to tetracycline, macrolide-lincosamide-streptogramin, trimethoprim, and sulfonamide drug classes

The discovery and use of antimicrobial agents in the last 50 yr has been one of medicine’s greatest achievements. These agents have reduced morbidity and mortality of humans and animals and have directly contributed to human’s increased life span. However, bacteria are becoming increasingly resistant to these agents by mutations, which alter existing bacterial proteins, and/or acquisition of new genes, which provide new proteins. The latter are often associated with mobile elements that can be exchanged quickly across bacterial populations and may carry multiple antibiotic genes fo resistance. In some case, virulence factors are also found on these same mobile elements. There is mounting evidence that antimicrobial use in agriculture, both plant and animal, and for environmental purposes does influence the antimicrobial resistant development in bacteria important in humans and in reverse. In this article, we will examine the genes which confer resistance to tetracycline, macrolide-lincosamide-streptogramin (MLS), trimethoprim, and sulfonamide.     

LAMP: A Database Linking Antimicrobial Peptides

The frequent emergence of drug-resistant bacteria has created an urgent demand for new antimicrobial agents. Traditional methods of novel antibiotic development are almost obsolete. Antimicrobial peptides (AMPs) are now regarded as a potential solution to revive the traditional methods of antibiotic development, although, until now, many AMPs have failed in clinical trials. A comprehensive database of AMPs with information about their antimicrobial activity and cytotoxicity will help promote the process of finding novel AMPs with improved antimicrobial activity and reduced cytotoxicity and eventually accelerate the speed of translating the discovery of new AMPs into clinical or preclinical trials. LAMP, a database linking AMPs, serves as a tool to aid the discovery and design of AMPs as new antimicrobial agents. The current version of LAMP has 5,547 entries, comprising 3,904 natural AMPs and 1,643 synthetic peptides. The database can be queried using either simply keywords or combinatorial conditions searches. Equipped with the detailed antimicrobial activity and cytotoxicity data, the cross-linking and top similar AMPs functions implemented in LAMP will help enhance our current understanding of AMPs and this may speed up the development of new AMPs for medical applications. LAMP is freely available at: http://biotechlab.fudan.edu.cn/database/lamp.     

Structure-based studies on species-specific inhibition of thymidylate synthase

Thymidylate synthase (TS) is a well-recognized target for anticancer chemotherapy. Due to its key role in the sole de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is an essential enzyme in all life forms. As such, it has been recently recognized as a valuable new target against infectious diseases. There is also a pressing need for new antimicrobial agents that are able to target strains that are drug resistant toward currently used drugs. In this context, species specificity is of crucial importance to distinguish between the invading microorganism and the human host, yet thymidylate synthase is among the most highly conserved enzymes. We combine structure-based drug design with rapid synthetic techniques and mutagenesis, in an iterative fashion, to develop novel antifolates that are not derived from the substrate and cofactor, and to understand the molecular basis for the observed species specificity. The role of structural and computational studies in the discovery of nonanalog antifolate inhibitors of bacterial TS, naphthalein and dansyl derivatives, and in the understanding of their biological activity profile, are discussed.     

Lurking in the shadows: emerging rodent infectious diseases

Rodent parvoviruses, Helicobacter spp., murine norovirus, and several other previously unknown infectious agents have emerged in laboratory rodents relatively recently. These agents have been discovered serendipitously or through active investigation of atypical serology results, cell culture contamination, unexpected histopathology, or previously unrecognized clinical disease syndromes. The potential research impact of these agents is not fully known. Infected rodents have demonstrated immunomodulation, tumor suppression, clinical disease (particularly in immunodeficient rodents), and histopathology. Perturbations of organismal and cellular physiology also likely occur. These agents posed unique challenges to laboratory animal resource programs once discovered; it was necessary to develop specific diagnostic assays and an understanding of their epidemiology and transmission routes before attempting eradication, and then evaluate eradication methods for efficacy. Even then management approaches varied significantly, from apathy to total exclusion, and such inconsistency has hindered the sharing and transfer of rodents among institutions, particularly for genetically modified rodent models that may not be readily available. As additional infectious agents are discovered in laboratory rodents in coming years, much of what researchers have learned from experiences with the recently identified pathogens will be applicable. This article provides an overview of the discovery, detection, and research impact of infectious agents recently identified in laboratory rodents. We also discuss emerging syndromes for which there is a suspected infectious etiology, and the unique challenges of managing newly emerging infectious agents.     

Genetic strategies for antibacterial drug discovery

The availability of genome sequences is revolutionizing the field of microbiology. Genetic methods are being modified to facilitate rapid analysis at a genome-wide level and are blossoming for human pathogens that were previously considered intractable. This revolution coincided with a growing concern about the emergence of microbial drug resistance, compelling the pharmaceutical industry to search for new antimicrobial agents. The availability of the new technologies, combined with many genetic strategies, has changed the way that researchers approach antibacterial drug discovery.     

Molecular strategies for overcoming antibiotic resistance in bacteria

Overuse of antibiotics in humans and livestock has led to the rapid evolution of bacteria that are resistant to multiple drugs such that even vancomycin, the drug of last resort, is no longer effective against some strains. Apart from the discovery and exploitation of the natural peptide antimicrobial agents that form part of the innate immune systems of plants and animals, there have been few new antibiotics developed in recent years. Here we review strategies designed to exploit recent advances in molecular biology, including recombinant DNA technology, molecular modelling and genomics to develop new antibacterial agents that overcome antibiotic resistance.     

Role of antimicrobial peptides in host defense against mycobacterial infections

Worldwide, tuberculosis remains the most important infectious disease causing morbidity and death. Currently, at least one-third of the world's population is infected with Mycobacterium tuberculosis. In addition, the World Health Organization estimates that about 8-10 million new tuberculosis cases occur annually worldwide and this incidence is currently increasing. Moreover, multidrug-resistant tuberculosis has been increasing in incidence in many areas during the past decade. These situations underscore the importance of the development of new therapeutic agents against mycobacterial infectious diseases. In this article, it is review current progress in the understanding of antimicrobial peptides as potential candidates to develop an alternative/adjunct therapeutic strategy against tuberculosis. This immunoadjunctive therapy might be evaluated in the context of possible drug resistance. This review also summarizes the knowledge about the functions of antimicrobial peptides in the pulmonary innate host defense system and their role in mycobacterial infection, and at the same time outlines recent advances in our understanding of the combined effect of antimicrobial peptides and anti-tuberculosis drugs against intracellular mycobacteria. A concerted effort should now focus on the clinical application of antimicrobial peptides for their practical use.     

An ancient solution to a modern problem

The dearth of new antibiotics and escalating emergence of multidrug resistant bacteria have created a global healthcare crisis and highlight the drastic need for novel antimicrobial agents. Complementary and alternative strategies including the investigation of ancient medicinals could address this problem. Natural clay minerals with a long history of medicinal and biomedical applications have become an interest due to their broad-spectrum antimicrobial activity. Such untapped natural sources may provide new therapeutic agents in the battle against infectious diseases in the post-antibiotic era.     

The future of new oral antibiotics including the quinolones.

It is estimated that more than 110 million dollars'' worth of oral antibiotics will have been sold in Canada in 1987. In the next few years several new oral antimicrobial agents will reach the market, including beta-lactamase inhibitors, cephalosporins, monobactams, erythromycins and quinolones. Most of these new agents have a broader spectrum of antibacterial activity than the presently available oral antibiotics. A few have a longer half-life and can be administered once a day. The new oral drugs, especially the quinolones and possibly beta-lactams, will now be used to treat infections that in the past could be treated only parenterally. Exacerbations of pulmonary infections due to Pseudomonas aeruginosa in cystic fibrosis can now be successfully treated at home with the new quinolones. Osteomyelitis, arthritis, pneumonia and pyelonephritis will most likely be treated at home in the future. In severe infections patients will be admitted to hospital for short courses of parenteral therapy, followed by oral treatment. If used appropriately the new oral agents may lead to new approaches to the treatment of infectious diseases.     

Seeing is believing: the impact of structural genomics on antimicrobial drug discovery

Over the past decade, the availability of complete microbial genome sequences has led to changes in the strategies that are used to search for novel anti-infectives. However, despite the identification of many new potential drug targets, novel antimicrobial agents have been slow to emerge from these efforts. In part, this reflects the long discovery and development times that are needed to bring new drugs to market and the bottlenecks at the stages of identifying good lead compounds and optimizing these leads into drug candidates. Structural genomics will hopefully provide opportunities to overcome these bottlenecks and populate the antimicrobial pipeline.     

Small and lethal: searching for new antibacterial compounds with novel modes of action.

The discovery of drugs used to combat infectious diseases is in the process of constant change to address the ever-worsening problem of antibiotic resistance in pathogens and a lack of recent success in discovering new antibacterial drugs. In the past 2 decades, research in both academia and industry has made use of molecular biology, genetics, and comparative genomics, which has led to the development of key technologies for the discovery of novel antibacterial agents. Genome-scale efforts have led to the identification of numerous molecular targets. Chemical diversity from synthetic combinatorial libraries and natural products is being used to screen for new molecules. A wide variety of approaches are being used in the search for novel antibiotics, and these can be categorized as being either biochemically focused or cell based. The over-riding goal of all methods in use today is to discover new chemical matter with novel mechanisms of action against drug-resistant pathogens.     

Serendipity and new drugs for infectious disease

Serendipity, in various shades of semantic legitimacy, is abundantly evident in the history of the chemotherapy of infectious disease. We may be on the threshold of a new era of rational drug design, but most medications for infectious diseases have arisen, and continue to arise, from chance observation, clinical experience, and the empirical search for substances active against pathogens. Chance does not produce drugs; but where chance has played a pivotal role in drug discovery, the event may be considered serendipitous to a greater or lesser degree. In a deliberate search for new drugs, it is often difficult to assess the degree to which any resulting discovery is serendipitous, and the usefulness of the term becomes debatable. Many therapeutic advances emerge from research involving animals, and a triggering "happy accident" may reside in the most basic aspects of animal care or in the most arcane knowledge of animals. The examples discussed in this article deal mostly with parasitic disease and the use of animal models in the discovery of antiparasitic agents. In this area, as in others, chance has laid the groundwork for scientific advancement and practical benefit. Although the applicability of the word serendipity to drug discovery may often be uncertain, the role played by chance should be recognized and welcomed.     

Leucocyte-transforming Agent from Mononucleosis is Ether-stable

SEVERAL agents are known to transform human lymphocytes. Co-cultivation with lethally irradiated cells from Burkitt's lymphoma will transform lymphocytes but so will cell free filtrates prepared from lymphoid cells killed by radiation or by freeze-thawing^1–9. Throat washing from several infectious mononucleosis patients also contained the lymphocyte transforming agent(s)¹⁰. Our study dealt with the transforming agents from mononucleosis and in particular with our discovery that the agents are not destroyed by ether. This discovery is unexpected and surprising because the transforming agents associated with other cell lines are believed to be the Epstein-Barr virus (EBV), a herpesvirus, the infectivity of which is destroyed by ether.     

The biology and future prospects of antivirulence therapies

The emergence and increasing prevalence of bacterial strains that are resistant to available antibiotics demand the discovery of new therapeutic approaches. Targeting bacterial virulence is an alternative approach to antimicrobial therapy that offers promising opportunities to inhibit pathogenesis and its consequences without placing immediate life-or-death pressure on the target bacterium. Certain virulence factors have been shown to be potential targets for drug design and therapeutic intervention, whereas new insights are crucial for exploiting others. Targeting virulence represents a new paradigm to empower the clinician to prevent and treat infectious diseases.