Showing papers by "Ian Chopra published in 2011"

Targeting bacterial membrane function: an underexploited mechanism for treating persistent infections

Abstract: Persistent infections involving slow-growing or non-growing bacteria are hard to treat with antibiotics that target biosynthetic processes in growing cells. Consequently, there is a need for antimicrobials that can treat infections containing dormant bacteria. In this Review, we discuss the emerging concept that disrupting the bacterial membrane bilayer or proteins that are integral to membrane function (including membrane potential and energy metabolism) in dormant bacteria is a strategy for treating persistent infections. The clinical applicability of these approaches is exemplified by the efficacy of lipoglycopeptides that damage bacterial membranes and of the diarylquinoline TMC207, which inhibits membrane-bound ATP synthase. Despite some drawbacks, membrane-active agents form an important new means of eradicating recalcitrant, non-growing bacteria.

Discovery research: the scientific challenge of finding new antibiotics

Abstract: The dwindling supply of new antibiotics largely reflects regulatory and commercial challenges, but also a failure of discovery. In the 1990s the pharmaceutical industry abandoned its classical ways of seeking antibiotics and instead adopted a strategy that combined genomics with high-throughput screening of existing compound libraries. Too much emphasis was placed on identifying targets and molecules that bound to them, and too little emphasis was placed on the ability of these molecules to permeate bacteria, evade efflux and avoid mutational resistance; moreover, the compound libraries were systematically biased against antibiotics. The sorry result is that no antibiotic found by this strategy has yet entered clinical use and many major pharmaceutical companies have abandoned antibiotic discovery. Although a raft of start-up companies-variously financed by venture capital, charity or public money--are now finding new antibiotic compounds (some of them very promising in vitro or in early trials), their development through Phase III depends on financial commitments from large pharmaceutical companies, where the discouraging regulatory environment and the poor likely return on investment remain paramount issues.

The urgent need for new antibacterial agents

Abstract: I find it continually amazing that society as a whole does not recognize the consequences of rising antimicrobial resistance as the threat it most certainly is. This is not for a lack of sustained activity by those who share these concerns. Far from it. Since 1997 there have been a plethora of enquiries, reports and recommendations—many from important bodies in both Europe and North America, yet little meaningful action has materialized. Some might consider this to be rather negative and an overstatement, yet can they point out a concrete outcome to all this activity? I like to think that the UK has led the way in raising concerns that antibiotic use, especially overuse (in animals as well as man) will hasten the day when these essential agents will lose their efficacy. The Swann Committee first brought this to our attention in 1969, and in 1998 a House of Lords report starkly stated that antimicrobial resistance was a ‘major threat to public health’. Most recently, the Infectious Diseases Society of America (IDSA) and the European Union, among others, have voiced their concerns. In 2009 the WHO called antibiotic resistance one of the three greatest threats to human health, and in 2011 the focus of World Health Day was ‘Combating Antibiotic Resistance’. However, antimicrobial resistance moves on in an inexorable fashion and the prospects for new agents are as bleak as ever. Perhaps it is us, the health professionals, who are at fault, either in the nature of our message, or in approaching the wrong groups who cannot influence outcomes? The BSAC has changed tack in its report on ‘The Urgent Need’, as outlined in the articles accompanying this one. – 9 Rather than restate the concerns surrounding antimicrobial resistance, its surveillance and how it might be contained (or more accurately, how its progress might be slowed), the BSAC adopted a different approach, focusing on the barriers to discovery and development of new technologies that might combat resistance (including new antimicrobial agents) and how these might be overcome. The Working Party of the BSAC examined three areas, namely research, regulation and economics. While recognizing that these areas are not distinct and there is much important overlap, the Working Party was challenged to suggest a practical framework for action. Critically there was an awareness on the part of the Working Party that the BSAC cannot undertake this immense task on its own, and co-operation with others is key. I do not wish to précis the report here, but rather make some personal comments on what I consider to be a few important areas. In research there is a major concern that international expertise in natural product discovery is being rapidly lost—how long has it been since such an antibacterial compound has been marketed? Overoptimism in genomics and highthroughput screening as the answer to the discovery of new agents in the 1990s would appear to have put back the cause by at least a decade. Research into how to influence the public’s perceptions of the risks confronting them (hence the political response) is also needed. Most certainly the regulatory issues relating to the licensing of new antimicrobials are extremely important. The bureaucrats are risk averse, yet do not take account of the risks to society of their inaction. This would change if political concerns were more loudly voiced. It is my personal opinion that it is changes in the economic field that are most likely to yield results. We were not the first to expound the economic arguments. Everything the Working Party heard from industry makes me believe that the marketplace must change. A course of antibiotics costs a few pounds or dollars and can save lives. In hospital practice we shudder if the costs rise into the hundreds. The angiogenesis inhibitor bevacizumab (trade name Avastin) is one of the most expensive widely marketed drugs. In 2008 sales generated nearly US$2.7 billion for Genentech, yet it has only modest effects on patient survival in a number of cancers. This is not to say it should not be used, but rather that there should be a rebalancing of risks and, more importantly, benefits. I would suggest that antimicrobials (other than a few antifungals) should be at a higher premium. Antimicrobial development must allow pharmaceutical companies realistic returns on their investment. This is crucial if society is to obtain new agents. So what actions should the BSAC undertake? The Working Party has suggested a number of short-, mediumand long-term activities. These, realistically, revolve around communication, in its broadest sense, with clinicians and academics, but possibly more importantly, with opinion formers in the UK and further afield. Such a programme of work, which will not be cheap, should include other parties and could usefully include the participation of the pharmaceutical industry.

Characterization of Global Patterns and the Genetics of Fusidic Acid Resistance

Abstract: Fusidic acid binds to elongation factor G (EF-G), preventing its release from the ribosome, thus stalling bacterial protein synthesis. In staphylococci, high-level fusidic acid resistance is usually caused by mutations in the gene encoding EF-G, fusA, and low-level resistance is generally caused by the horizontally transferable mechanisms fusB and fusC that have a putative protective role on EF-G. In addition, fusD is responsible for intrinsic resistance in Staphylococcus saprophyticus, and alterations in the L6 portion of rplF (fusE) have a role in fusidic acid resistance. Fusidic acid has been used in Europe and Australia for decades. More recently, it has also been used in other countries and regions, but not in the United States. Worldwide fusidic acid resistance has been slow to develop, and the level of resistance and genetic mechanisms responsible generally reflect the time since introduction, indications for treatment, route of administration, and prescribing practices.

Effective antibacterials: at what cost? The economics of antibacterial resistance and its control

Abstract: The original and successful business model of return on investment being sufficiently attractive to the pharmaceutical industry to encourage development of new antibacterial molecules and related diagnostics has been compromised by increasing development costs and regulatory hurdles, resulting in a decreasing chance of success and financial return. The supply of new effective agents is diminishing along with the number of companies engaged in antibacterial research and development. The BSAC Working Party on The Urgent Need:Regenerating Antibacterial Drug Discovery and Development identified the need to establish, communicate and apply the true health and economic value of antibacterials, along with the adoption of meaningful incentives, as part of the future model for antibacterial development. Robust data are needed on the cost of resistance and ineffective treatment of bacterial infection, along with national and local holistic analyses of the cost-benefit of antibacterials. An understanding of the true health and economic value of antibacterials and the cost of resistance across healthcare systems needs to be generated, communicated and used in order to set a pricing and reimbursement structure that is commensurate with value. The development and economic model of antibacterial use needs to be rebuilt based on this value through dialogue with the various stakeholders, including the pharmaceutical industry, and alternative incentives from 'push' to 'pull' and funding models, such as public/private partnerships, agreed. A research and development model that succeeds in developing and delivering new antibacterial agents that address the health needs of society from start to finish, 'from cradle to grave', must be established.

Distribution of Fusidic Acid Resistance Determinants in Methicillin-Resistant Staphylococcus aureus

Abstract: The prevalence of resistance to fusidic acid in clinical isolates of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), has increased in the past 2 decades. However, there are limited data regarding the relative importance in this process of the different staphylococcal determinants that mediate resistance to fusidic acid. Furthermore, the roles played by clonal dissemination of fusidic acid-resistant strains versus horizontal transmission of fusidic acid resistance determinants have not been investigated in detail. To gain insight into both issues, we examined fusidic acid resistance in 1,639 MRSA isolates collected in Denmark between 2003 and 2005. Resistance to fusidic acid (MIC, >1 μg/ml) was exhibited by 291 (17.6%) isolates. For the majority of these isolates (∼87%), resistance was attributed to carriage of fusB or fusC, while the remainder harbored mutations in the gene (fusA) encoding the drug target (EF-G). The CC80-MRSA-IV clone carrying fusB accounted for ∼61% of the resistant isolates in this collection, while a single CC5 clone harboring fusC represented ∼12% of the resistant strains. These findings emphasize the importance of clonal dissemination of fusidic acid resistance within European MRSA strains. Nonetheless, the distribution of fusB and fusC across several genetic lineages, and their presence on multiple genetic elements, indicates that horizontal transmission of fusidic acid resistance genes has also played an important role in the increasing prevalence of fusidic acid resistance in MRSA.

Activity of and Development of Resistance to Corallopyronin A, an Inhibitor of RNA Polymerase

Abstract: We explored the properties of corallopyronin A (CorA), a poorly characterized inhibitor of bacterial RNA polymerase (RNAP). It displayed a 50% inhibitory concentration of 0.73 μM against RNAP, compared with 11.5 nM for rifampin. The antibacterial activity of CorA was also inferior to rifampin, and resistant mutants of Staphylococcus aureus were easily selected. The mutations conferring resistance resided in the rpoB and rpoC subunits of RNAP. We conclude that CorA is not a promising antibacterial drug candidate.

Structure-based ligand design of novel bacterial RNA polymerase inhibitors.

Abstract: Bacterial RNA polymerase (RNAP) is essential for transcription and is an antibacterial target for small molecule inhibitors. The binding region of myxopyronin B (MyxB), a bacterial RNAP inhibitor, offers the possibility of new inhibitor design. The molecular design program SPROUT has been used in conjunction with the X-ray cocrystal structure of Thermus thermophilus RNAP with MyxB to design novel inhibitors based on a substituted pyridyl-benzamide scaffold. A series of molecules, with molecular masses <350 Da, have been prepared using a simple synthetic approach. A number of these compounds inhibited Escherichia coli RNAP.

Regulatory opportunities to encourage technology solutions to antibacterial drug resistance

Abstract: Regulatory agencies play a critical role in the licensing of new antimicrobial agents. To address the pivotal role played by regulatory agencies, particularly in the context of a paucity of new drugs active against bacteria resistant to currently available drugs, the BSAC formed the 'Urgent Need' Working Party to address the regeneration of antibacterial drug discovery and development. The Working Party identified a number of issues, including: increased application of pharmacokinetic/pharmacodynamic principles to expedite drug development; the need to prioritize licensing of drugs (including 'orphan' drugs) active in life-threatening infections; and expansion of the use of surrogate markers and rapid point of care diagnostics to facilitate drug development.

Further Characterization of Bacillus subtilis Antibiotic Biosensors and Their Use for Antibacterial Mode-of-Action Studies

Abstract: We further examined the usefulness of previously reported Bacillus subtilis biosensors for antibacterial mode-of-action studies. The biosensors could not detect the tRNA synthetase inhibitors mupirocin, indolmycin, and borrelidin, some inhibitors of peptidoglycan synthesis, and most membrane-damaging agents. However, the biosensors confirmed the modes of action of several RNA polymerase inhibitors and DNA intercalators and provided new insights into the possible modes of action of ciprofloxacin, anhydrotetracycline, corralopyronin, 8-hydroxyquinoline, and juglone.