Infectious Disorders - Drug Targets
(Formerly 'Current Drug Targets - Infectious Disorders')

ISSN: 1871-5265

Infectious Disorders – Drug Targets
Volume 7, Number 1, March 2007

Contents


Editorial: Infectious Diseases: What is in our Future? Pp. 1-2
Robert C. Goldman


Exploring DNA Topoisomerases as Targets of Novel Therapeutic Agents in the Treatment of Infectious Diseases Pp. 3-9
Y.-C. Tse-Dinh
[Abstract] [Full Text Article]


Novel Targets for the Development of Anti-Herpes Compounds Pp. 11-18
A. Greco, J-J. Diaz, D. Thouvenot and F. Morfin
[Abstract] [Full Text Article]


Targeting Bacterial Secretion Systems: Benefits of Disarmament in the Microcosm Pp. 19-27
Christian Baron and Brian Coombes
[Abstract] [Full Text Article]


Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus Pp. 29-41
Kap-Sun Yeung and Nicholas A. Meanwell
[Abstract] [Full Text Article]


Antibiotic Resistance During Therapy: Mechanisms and Means of Control Pp. 43-45
J. C. Rodríguez, E. Pastor, M. Ruiz, E. Flores and G. Royo
[Abstract] [Full Text Article]


Strategies to Design Inhibitors of Clostridium Botulinum Neurotoxins Pp. 47-57
S. Cai and B. R. Singh
[Abstract] [Full Text Article]


Antiviral Strategies Against Human Coronaviruses Pp. 59-66
K. Pyrc, B. Berkhout and L. van der Hoek
[Abstract] [Full Text Article]


Human Defensins: Turning Defense into Offense? Pp. 67-70
Erik de Leeuw and Wuyuan Lu
[Abstract] [Full Text Article]




Abstracts

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Editorial

Infectious Diseases: What is in our Future?

Current Drug Targets-Infectious Disorders (CDT-ID) was launched in May of 2001 and is now starting its seventh year with the March 2007 issue, although under a new name: Infectious Disorder - Drug Targets. Special Topics issues, organized by a Guest Editor, are published twice a year and have been well received since their inception in 2001. Two Special Topics issues are scheduled for 2007: 1) Drs. Robert Goldman and Barbara Laughon (Complications and Coinfections Research Branch, National Institutes of Health, Bethesda, MD) will be the Guest Editors of our June 2007 Special Topics issue on Tuberculosis Targets and Drug Discovery and Development; and 2) Dr. Christopher F. Basler (Mount Sinai School of Medicine) will be the Guest Editor of our December 2007 Special Topics issue on Influenza Virus Epidemics and Drug Targets.

Someone dies of tuberculosis (TB) every 15 seconds, and in spite of global control and treatment efforts some regions of the world are experiencing a crisis that will likely spread. The discovery of streptomycin in the 1943 by the Nobel Laureate Selman Waksman’s group at Rutgers University and subsequent demonstration of its efficacy against TB proved that effective chemotherapy could be administered. However, in only a few years of clinical use the specter of resistance arose and became a major concern. Today we have to deal with multi-drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) strains. MDR-TB strains are defined as those resistant to both isoniazid and rifampicin, two of the most effective first-line drugs. XDR-TB was initially defined as MDR-TB with further resistance to three or more of the six main classes of second-line antitubercular drugs (aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine and para-aminosalicylic acid). This definition was changed to resistance to isoniazid and rifampicin plus resistance to any fluoroquinolone and at least one of three injectable second-line drugs (amikacin, kanamycin, or capreomycin). Regardless of semantic definitions, multiple drug resistance in TB has led to a developing global health-care crisis over the past decade, one that was brought to the forefront when a deadly outbreak of XDR-TB occurred in a rural area in KwaZulu Natal, South Africa. The initial report described infection in 53 persons (44 know to be HIV positive) that lead to death in 52 of 53 patients with a median survival of 16 days from time of diagnosis (Neel R Gandhi, Anthony Moll, A Willem Sturm, Robert Pawinski, Thiloshini Govender, Umesh Lalloo, Kimberly Zeller, Jason Andrews, Gerald Friedland, The Lancet Vol. 368, November 4, 2006, page 1575). Since then the outbreak has increased to over 500 known cases. A more detailed review of XDR-TB will appear in the June 2007 Special Topics issue.

The March 2007 issue of Infectious Disorders - Drug Targets presents a range of topics covering many exciting developments in infectious disease research.

Targeting Bacterial Secretion Systems: Benefits of Disarmament in the Microcosm (C. Baron and B. Coombes): Bacterial pathogens use specialized secretion systems to deliver virulence factors temporally and spatially in the infected host. The assembly and function of type II, type III and type IV secretion systems in Gram-negative bacteria are reviewed in the context of structure and function, as well as strategies for identifying potential inhibitors.

Novel Targets for the Development of Anti-herpes Compounds (A. Greco, J-J Diaz, D. Thouvenot and F. Morfin): Herpes simplex (HSV) viruses represent a major infectious disease problem for millions of people, especially those who are immunocompromised. Reliance on a single agent, acyclovir, as the major therapy has led to resistance selection. Viral and cellular targets involved in HSV replication and infection are reviewed along with progress in discovering new inhibitory agents.

Antibiotic Resistance during Therapy: Mechanisms and Means of Control (J. C. Rodríguez, E. Pastor, M. Ruiz, E. Flores, and G. Royo): The continued evolution and dissemination of drug resistant bacteria is a major health care burden. The complex microbiological factors involved in the selection of resistance during antibiotic therapy are reviewed, along with approaches to minimize selection of resistance in the future.

Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus (K-S Yeung and N. A. Meanwell): This comprehensive review focuses on the recent advances in our understanding of SARS, a deadly disease caused by a coronavirus. Progress in identifying new targets and lead compounds is reviewed. SARS was a global threat in 2003 over 5000 reported cases and a case fatality rate of 10-20%. Recent unconfirmed reports claim SARS reemergence in China in 2007.

Exploring DNA Topoisomerases as Targets of Novel Therapeutic Agents in the Treatment of Infectious Diseases (Y.-C. Tse-Dinh): Topoisomerases are involved in many critical cellular processes and have been targets for infectious disease and cancer therapies. The various forms of topoisomerase, their role in cellular function, and approaches to targeting with small molecules are reviewed.

Strategies to Design Inhibitors of Clostridium botulinum Neurotoxins (S. Cai and B. R. Singh): Bacterial toxins are involved in the pathogenesis of many diseases, and are also considered possible weapons for bio-warfare. The structure and function of botulinum toxin and approaches to abrogating its toxic effects are reviewed, including the possible use of aptamer technology.

Human Defensins: Turning Defense Into Offense? (E. de Leeuw and W. Lu): Potent antimicrobial peptides (defensins) are a first line of defense against microbial pathogens in many infected hosts. The role of defensins in innate and adaptive immunity is reviewed along with approaches to developing novel, defensin-based therapeutics.

Antiviral Strategies against Human Coronaviruses (K. Pyrc, B. Berkhout, and L. van der Hoek): Although human coronoviruses have been known for decades, the realization of their potential for causing human disease was not realized until the 2002-2003 outbreaks of SARS. Other coronoviruses also are known to cause disease in immunocompromized patients. The biology of coronoviruses is reviewed along with the seach for new antiviral agents.

The future of antimicrobial therapy may change rapidly for the worse over the next several decades, given the continual increase in drug resistance and the fact that several large pharmaceutical companies have reduced efforts in their antibiotic discovery programs. Although many smaller biotechnology companies continue to invest in antimicrobial drug discovery, their efforts may not be sufficient to discover and develop the novel agents that will be required for the treatment of drug resistant infectious diseases. What is in our future? Pan-drug resistant TB? A return to TB sanatoriums? The Adirondack Cottage Sanatorium (often called the Little Red Cottage) was the first opened in 1884 (Saranac Lake, New York) by the physician Edward Livingston Trudeau (1848-1915) who himself contracted TB during his medical training. In the following years the number of sanatoriums grew to over 700 in the United States alone.

This preface was written by Robert C. Goldman in his personal capacity (as Editor-in Chief of Current Drug Targets-Infectious Disorders). The views expressed herein do not necessarily represent the views of NIH, DHHS, or the United States.


Robert C. Goldman
Editor-in-Chief
Infectious Disorders - Drug Targets
March 2007


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Exploring DNA Topoisomerases as Targets of Novel Therapeutic Agents in the Treatment of Infectious Diseases
Y.-C. Tse-Dinh

[Full Text Article]

DNA topoisomerases are ubiquitous enzymes needed to overcome topological problems encountered during DNA replication, transcription, recombination and maintenance of genomic stability. They have proved to be valuable targets for therapy, in part because some anti-topoisomerase agents act as poisons. Bacterial DNA gyrase and topoisomerase IV (type IIA topoisomerases) are targets of fluoroquinolones while human topoisomerase I (a type IB topoisomerase) and topoisomerase II are targets of various anticancer drugs. Bacterial type IA topoisomerase share little sequence homology to type IB or type IIA topoisomerases, but all topoisomerases have the potential of having the covalent phosphotyrosine DNA cleavage intermediate trapped by drug action. Recent studies have demonstrated that stabilization of the covalent complex formed by bacterial topoisomerase I and cleaved DNA can lead to bacterial cell death, supporting bacterial topoisomerase I as a promising target for the development of novel antibiotics. For current antibacterial therapy, the prevalence of fluoroquinolone-resistant bacterial pathogens has become a major public health concern, and efforts are directed towards identifying novel inhibitors of bacterial type IIA topoisomerases that are not affected by fluoroquinolone resistant mutations on the gyrase or topoisomerase IV genes. For anti-viral therapy, poxviruses encode their own type IB topoisomerases; these enzymes differ in drug sensitivity from human topoisomerase I. To confront potential threat of small pox as a weapon in terrorist attacks, vaccinia virus topoisomerase I has been targeted for discovery of anti-viral agents. These new developments of DNA topoisomerases as targets of novel therapeutic agents being reviewed here represent excellent opportunities for drug discovery in the treatment of infectious diseases.


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Novel Targets for the Development of Anti-Herpes Compounds
A. Greco, J-J. Diaz, D. Thouvenot and F. Morfin

[Full Text Article]

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are members of the Herpesviridae family. HSV infections have been known since ancient times and are one of the most common communicable diseases in humans. Although infections are often subclinical, HSV can cause mild to severe diseases, especially in immunocompromised patients. Herpes simplex viruses establish latency in the nuclei of neuronal cells and may reactivate, with or without symptoms, throughout the host's lifetime. Over one third of the world's population suffer from recurrent HSV infections several times a year and are thus capable of transmitting HSV by close personal contact.

There are few drugs licensed for the treatment of HSV infections. Most target the viral DNA polymerase, and indeed acyclovir remains the reference treatment some thirty years after its discovery! Extensive clinical use of this drug has led to the emergence of resistant viral strains, mainly in immunocompromised patients. This highlights the crucial need for the development of new anti-herpes drugs that can inhibit infection by both wild-type viruses and drug-resistant strains.

Over the last few years, significant efforts have been made to set up a range of strategies for the identification of potential new anti-viral drugs. One alternative is to develop drugs with different mechanisms of action. The present article reviews potential viral and cellular targets that are now known to be involved in HSV infection and for which specific inhibitors with anti-HSV activity, at least in cell culture, have been identified.


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Targeting Bacterial Secretion Systems: Benefits of Disarmament in the Microcosm
Christian Baron and Brian Coombes

[Full Text Article]

Secretion systems are used by many bacterial pathogens for the delivery of virulence factors to the extracellular space or directly into host cells. They are attractive targets for the development of novel anti-virulence drugs as their inactivation would lead to pathogen attenuation or avirulence, followed by clearance of the bacteria by the immune system. This review will present the state of knowledge on the assembly and function of type II, type III and type IV secretion systems in Gram-negative bacteria focusing on insights provided by structural analyses of several key components. The suitability of transcription factors regulating the expression of secretion system components and of ATPases, lytic transglycosylases and protein assembly factors as drug targets will be discussed. Recent progress using innovative in vivo as well as in vitro screening strategies led to a first set of secretion system inhibitors with potential for further development as anti-infectives. The discovery of such inhibitors offers exciting and innovative opportunities to further develop these anti-virulence drugs into monotherapy or in combination with classical antibiotics. Bacterial growth per se would not be inhibited by such drugs so that the selection for mutations causing resistance could be reduced. Secretion system inhibitors may therefore avoid many of the problems associated with classical antibiotics and may constitute a valuable addition to our arsenal for the treatment of bacterial infections.


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Recent Developments in the Virology and Antiviral Research of Severe Acute Respiratory Syndrome Coronavirus
Kap-Sun Yeung and Nicholas A. Meanwell

[Full Text Article]

This article summarizes the significant developments and new discoveries in both the virology and antiviral research associated with the severe acute respiratory syndrome coronavirus (SARS CoV) that were reported in 2005 and 2006. Areas reviewed include genomic studies and the identification of bat-SARS CoV, spike protein and host cell entry, nucleocapsid protein, accessory proteins, non-structural proteins of the replicase complex, viral proteases and their inhibitors, and clinical treatment of SARS with ribavirin.


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Antibiotic Resistance During Therapy: Mechanisms and Means of Control
J. C. Rodríguez, E. Pastor, M. Ruiz, E. Flores and G. Royo

[Full Text Article]

Antibiotic resistance is a serious public health problem. The most effective way to control this phenomenon is to make rational use of antibiotics. However, antibiotic resistance is a complex process in which clinical, pharmacodynamic, pharmacokinetic and microbiological factors all play a part.

Since antibiotic therapy is usually performed empirically, clinicians should follow guidelines that take all these factors into account together with the concepts of evidence based medicine. These guidelines may be elaborated using information technology tools that help to collect, analyze and weigh up all the information available on a certain pathogen.

Therefore, the administration of antibiotics should be controlled with the help of multi-disciplinary working groups and in accordance with objective data collected following a thorough analysis of all the available information.


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Strategies to Design Inhibitors of Clostridium Botulinum Neurotoxins
S. Cai and B. R. Singh

[Full Text Article]

Botulinum neurotoxins (BoNTs), produced by spore-forming anaerobic Clostridium botulinum, are the most toxic substances known. They cause the life-threatening disease botulism, characterized by flaccid muscle paralysis. While the natural cases of botulism are rare, due to their extreme toxicity and easy production, BoNTs have become potential biowarfare agents, and create maximum fear among populations concerned with bioterror agents. The only available antidote against BoNTs is equine antitoxin. Equine antitoxin can only target the toxins at extracellular level, and can not reverse the paralysis caused by botulism. In addition, equine antibody can cause severe hypersensitivity reactions, and is limited to be used for prophylaxis treatment.

BoNTs are large proteins with three distinct domains, the binding domain, the translocation domain, and the enzymatic domain with highly specific endopeptidase activity to cleave the proteins involved the neurotransmitter release. Targeting any of these domains can inhibit the functions of BoNT. Humanized monoclonal antibodies, small peptides and peptide mimetics, receptor mimics, and small molecules targeting the endopeptidase activity have emerged as potential new inhibitors against BoNTs. With the structure of BoNT resolved, molecular modeling and rational design of potent antidotes against botulism is on the horizon. An area that has not been explored for designing the antidotes against botulism is aptamers, which have been successfully developed as therapeutics in several areas. This review will focus on some of these new strategies to design effective antidotes against botulism. The strategies reviewed in this article can be easily applied to design inhibitors for other bacterial toxins.


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Antiviral Strategies Against Human Coronaviruses
K. Pyrc, B. Berkhout and L. van der Hoek

[Full Text Article]

Since the mid 60’s the human coronaviruses (HCoV), represented by HCoV-OC43 and HCoV-229E, were generally considered relatively harmless viruses. This status changed dramatically with the emergence of SARS-CoV in 2002/2003. The SARS-CoV pandemic took 774 lives around the globe and infected more than 8000 people in 29 countries. SARS-CoV is believed to be of zoonotic origin, transmitted from its natural reservoir in bats through several animal species (e.g., civet cats, raccoon dogs sold for human consumption in markets in southern China). The epidemic was halted in 2003 by a highly effective global public health response, and SARS-CoV is currently not circulating in humans. The outbreak of SARS-CoV and the danger of its re-introduction into the human population, as well as the danger of the emergence of other zoonotic coronaviral infections triggered an intense survey for an efficient treatment that resulted in the evaluation of several anticoronaviral compounds.

HCoV-NL63 and HCoV-HKU1 were identified shortly after the SARS-CoV outbreak. The 4 human coronaviruses HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 cause mild respiratory illnesses when compared to SARS, but these infections are involved in 10 – 20 % of hospitalizations of young children and immunocompromised adults with respiratory tract illness. Therefore, there is an urgent need for a successful therapy to prevent disease induction or a vaccine to prevent new infections. This review summarizes the current status of anticoronaviral strategies.


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Human Defensins: Turning Defense into Offense?
Erik de Leeuw and Wuyuan Lu

[Full Text Article]

Defensins are a family of antimicrobial cationic peptides that act as a rapid response force against microbial invasion in a wide range of organisms, including plants, insects, animals and humans. In humans, defensins are produced predominantly by leukocytes and epithelial cells and are an important factor of innate immunity. In addition to their major role as natural antibiotics, defensins are increasingly recognized as signaling molecules in adaptive immunity and aberrant defensin expression has been associated with infectious diseases. In this review, we discuss the role of human defensins in relation to infectious disease and the possibility of novel defensin-based therapeutic approaches.