Editorial overviewDisruptive innovations: new anti-infectives in the age of resistance
Section snippets
A new chapter in the book of infectious diseases
The U.S. Surgeon General William H Stewart remarked in a 1969 statement to congress ‘The time has come to close the book on infectious disease’ [1]. The golden era of antibiotic discovery that had lasted from 1950 until 1970 was coming to an end. Even at that time some scientists were skeptical at such a bold statement, and doubted that a single technology could win the war against infectious disease, but then antibiotic resistance was more of a test-tube concept under laboratory investigation,
From ‘suberbugs’ to the ‘end of the antibiotic era’
At the present time multidrug resistant microbes account for the majority of nosocomial and community acquired infections and represent an exponentially growing threat to human health. These organisms have now dominated the scientific literature and have given rise to the term ‘superbugs’ [2]. Infectious disease in the 21st century is again at the epicenter of a global dialogue capturing the attention of academics, governments, public health officials, and the general public alike. Each year
Industry versus academia
A large fraction of the key player large companies in the pharmaceutical arena have abandoned their anti-infective research programs in the recent past. This trend is underlined by the observation that it is easier to name the few companies that still retain a program, even if it is not prioritized, than to enumerate those who have abandoned their anti-infective research. The reasons for the de-emphasis on industrial development of new antimicrobials can be categorized as perceptual (market
The riddle of antimicrobial resistance
Several mechanisms have evolved in microorganisms which confer antimicrobial resistance [8]. These mechanisms can either chemically modify the antimicrobial agent, render it inactive through physical removal from the cell, or modify the target site so that it is not recognized by the antimicrobial. Resistance may be an inherent trait of the organism (e.g. a particular type of cell wall structure) that renders it naturally resistant, or it may be acquired by means of mutation in its own DNA or
Natural antimicrobials
The first paper by Bologa et al. in the special issue covers advances in the development of natural product antimicrobials. Natural products and their analogs continue to play a prominent role in medicine, accounting for two-thirds of new antibacterial therapies approved from 1980 to 2010 as well as several antibacterials currently in clinical trials [11]. The efficacy of natural products as antibacterial agents likely stems from the fact that they have been honed by millennia of evolutionary
Quorum sensing inhibitors
Zhu and Kaufmann propose a novel antimicrobial approach based upon inhibiting or ‘quenching’ bacterial quorum sensing. Interference with quorum sensing signaling might offer new avenues to prevent and/or treat bacterial infections via inhibition of virulence factor expression and biofilm formation [12]. Prophylactic quorum quenching approaches have demonstrated efficacy in vivo. Quorum sensing antigens might warrant inclusion in microbial vaccination strategies. Combination of quorum quenching
Biologically inspired strategies for combating bacterial biofilms
Blackledge et al. discuss a range of strategies to combat bacterial biofilms, focusing firstly on small molecule interference with bacterial communication and signaling pathways, including quorum sensing and two-component signal transduction systems. Enzymatic approaches to the degradation of extracellular matrix components to effect biofilm dispersal are covered. Both these approaches are based upon non-microbicidal mechanisms of action, and thereby do directly exert selective pressure on the
Gallium based anti-infectives
Kelson et al. describe a novel antimicrobial approach based on the trivalent metal, gallium. Microbes have evolved elaborate iron-acquisition systems to sequester iron from the host environment using siderophores and heme uptake systems. Since gallium(III) is structurally similar to iron(III), except that it cannot be reduced under physiological conditions, gallium can behave as an iron analog, and thus an antimicrobial. Because Ga(III) can bind to virtually any complex that binds Fe(III), both
Cyclodextrin derivatives (CD) as anti-infectives
Karginov describes the use of CD to inhibit pore-forming proteins that are potent virulence factors produced by some pathogenic bacteria. Highly efficient selection of potent inhibitors was achieved since persubstituted cyclodextrins were found to possess the same symmetry as the target pores. Inhibitors of several bacterial toxins produced by B. anthracis, S. aureus, C. perfringens, C. botulinum and C. difficile were identified in a library of ∼200 CD. They demonstrated that multi-targeted
Anti-fungal therapy with an emphasis on biofilms
Pierce et al. discuss the increasing need for novel anti-fungal drugs. Since fungi are eukaryotic organisms there are a limited number of targets for anti-fungal drug development compared to prokaryotic or viral pathogens. Azoles, polyenes and echinocandins constitute the mainstay of anti-fungal therapy for patients with life-threatening mycoses. One of the main factors complicating anti-fungal therapy is the formation of fungal biofilms that provide resistance to most anti-fungal agents. A
Light based-antimicrobial strategies
Yin et al. cover a group of antimicrobial approaches, which all rely on light to deliver the killing blow. Although ultraviolet light has long been used as a germicidal treatment, its use as a therapeutic for infections has not been studies until recently when it was realized that the possible adverse effects to host tissue were relatively minor compared to its high activity in killing pathogens. Photodynamic therapy employs the combination of non-toxic dyes with harmless visible light that
Drosophila melanogaster as a model host
The last two papers in the Special Issue cover the use of non-vertebrate hosts for drug discovery of new antimicrobials. The first contribution by Tzelepis et al. concerns the fruitfly D. melanogaster. Drug screening in Drosophila offers to fill the gap between in vitro and mammalian model hosts by eliminating compounds that are toxic or have reduced bioavailability and by identifying others that may boost innate host defence or selectively reduce microbial virulence in a whole-organism
Caenorhabditis elegans for anti-infective drug discovery
The final contribution by Arvanitis et al. also covers another non-vertebrate host for drug discovery, in this case the nematode worm C. elegans. This alternative host has been used to identify traditional microbicidal agents, including antihelminthic compounds, as well as novel agents that attenuate microbial virulence or enhance the host's immune response. Its amenability to high-throughput automated screening can allow for the detection of bioactive products among thousands of tested
Conclusions and future perspectives
The early chemotherapeutic antimicrobials originated from synthetic chemistry (e.g. dye research), as embodied by sulfa drugs, in the early 1930s. Then followed the great era of antibiotic discovery, that quickly led to predictions of the end of infectious disease as a significant clinical problem. Increasing antibiotic resistance over the last 50 years turned this rosy outlook to a gloomy prognosis of untreatable infections waiting to pounce on any unsuspecting hospital patient. The articles
Acknowledgements
GPT is supported by US DTRA, HDTRA1-13-C-0005. MRH is supported by US NIH grant R01AI050875.
George P Tegos is an assistant professor at the Department of Pathology School of Medicine at the University of New Mexico affiliated with the Center of Molecular Discovery and a Visiting Scientist at the Wellman Center for Photomedicine at Massachusetts General Hospital, Harvard Medical School. He received his PhD from University of Ioannina, Greece. He completed postdoctoral fellowships in Molecular Microbiology (Antimicrobial Discovery Center at Northeastern University, 2001–2003) and
References (12)
Antimicrobial stewardship: concepts and strategies in the 21st century
Diagn Microbiol Infect Dis
(2008)- et al.
The antibiotic crisis
Super bugs: survival of the fittest
Adv Skin Wound Care
(2010)- et al.
Global antimicrobial resistance: from surveillance to stewardship, Part 1: surveillance and risk factors for resistance
Expert Rev Anti Infect Ther
(2012) - et al.
Clinical relevance of the ESKAPE pathogens
Expert Rev Anti Infect Ther
(2013) Antimicrobial resistance and aging: beginning of the end of the antibiotic era?
J Am Geriatr Soc
(2002)
Cited by (0)
George P Tegos is an assistant professor at the Department of Pathology School of Medicine at the University of New Mexico affiliated with the Center of Molecular Discovery and a Visiting Scientist at the Wellman Center for Photomedicine at Massachusetts General Hospital, Harvard Medical School. He received his PhD from University of Ioannina, Greece. He completed postdoctoral fellowships in Molecular Microbiology (Antimicrobial Discovery Center at Northeastern University, 2001–2003) and Translational Therapeutics in Dermatology (Wellman Center for Photomedicine, Harvard Medical School at Massachusetts General Hospital, 2003–2006). His research interests lies in the areas of drug discovery and development of antimicrobial strategies with emphasis in photodynamic therapy for infections, multidrug efflux systems as well as virulence and microbial pathogenesis. His research program is supported by the US National Institutes of Health, the Department of Defense (DOD-DTRA) and the Clinical and Translational Science Center at the University of New Mexico (CTSC-UNM). He has been an EU Marie Curie fellow in Biotechnology and a recipient of the Massachusetts Technology Transfer Center (MTTC) award in Antimicrobials. He has published over 65 peer-reviewed articles, over 80 conference proceedings, book chapters and International abstracts, served as an ad hoc reviewer for a variety of journals and funding organizations in US, Europe and Asia and has delivered more than 40 invited presentations.
Michael R Hamblin is a principal investigator at the Wellman Center for Photomedicine at Massachusetts General Hospital, an Associate Professor of Dermatology at Harvard Medical School and is a member of the affiliated faculty of the Harvard-MIT Division of Health Science and Technology. He was trained as a synthetic organic chemist and received his PhD from Trent University in England. His research interests lie in the areas of photodynamic therapy (PDT) for infections, cancer, and heart disease and in low-level light therapy (LLLT) for wound healing, arthritis, traumatic brain injury and hair regrowth. He directs a laboratory of around a 16 post-doctoral fellows, visiting scientists and graduate students. His research program is supported by NIH, CDMRP, USAFOSR and CIMIT among other funding agencies. He has published 232 peer-reviewed articles, over 150 conference proceedings, book chapters and International abstracts and holds eight patents. He is Associate Editor for seven journals, on the editorial board of a further 12 journals and serves on NIH Study Sections. For the past 9 years Dr Hamblin has chaired an annual conference at SPIE Photonics West entitled ‘Mechanisms for low level light therapy’ and he has edited the nine proceedings volumes together with two other major textbooks on PDT. He has several other book projects in progress at various stages of completion. In 2011 Dr Hamblin was honored by election as a Fellow of SP.