Summary Antibiotic use not only underpins modern medicine, but has brought huge changes to the world, especially in expectations of survival of children into adulthood. The theme of World Health Day, ...2011, was “antimicrobial resistance: no action today and no cure tomorrow”. The demise of antibacterial drug discovery brings the spectre of untreatable infections. To prevent this crisis immediate action is needed and a new initiative, Antibiotic Action, has been launched. By bringing together communities who need these drugs with academia, health-care professionals, and pharmaceutical companies, this initiative aims to strengthen and enhance academic-industrial partnerships, bring about revision of costly and laborious processes of licensing and regulation of new antibiotics, and address the economics of antimicrobial drugs (cost of use vs profit). A global alliance for antibiotic drug discovery and development would provide a platform for these initiatives.
Molecular mechanisms of antibiotic resistance Blair, Jessica M A; Webber, Mark A; Baylay, Alison J ...
Nature reviews. Microbiology,
01/2015, Letnik:
13, Številka:
1
Journal Article
Recenzirano
Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, ...many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.
Summary To combat the threat to human health and biosecurity from antimicrobial resistance, an understanding of its mechanisms and drivers is needed. Emergence of antimicrobial resistance in ...microorganisms is a natural phenomenon, yet antimicrobial resistance selection has been driven by antimicrobial exposure in health care, agriculture, and the environment. Onward transmission is affected by standards of infection control, sanitation, access to clean water, access to assured quality antimicrobials and diagnostics, travel, and migration. Strategies to reduce antimicrobial resistance by removing antimicrobial selective pressure alone rely upon resistance imparting a fitness cost, an effect not always apparent. Minimising resistance should therefore be considered comprehensively, by resistance mechanism, microorganism, antimicrobial drug, host, and context; parallel to new drug discovery, broad ranging, multidisciplinary research is needed across these five levels, interlinked across the health-care, agriculture, and environment sectors. Intelligent, integrated approaches, mindful of potential unintended results, are needed to ensure sustained, worldwide access to effective antimicrobials.
It is well established that multidrug-resistance efflux pumps encoded by bacteria can confer clinically relevant resistance to antibiotics. It is now understood that these efflux pumps also have a ...physiological role(s). They can confer resistance to natural substances produced by the host, including bile, hormones and host-defence molecules. In addition, some efflux pumps of the resistance nodulation division (RND) family have been shown to have a role in the colonization and the persistence of bacteria in the host. Here, I present the accumulating evidence that multidrug-resistance efflux pumps have roles in bacterial pathogenicity and propose that these pumps therefore have greater clinical relevance than is usually attributed to them.
The global challenges presented by drug-resistant bacterial infections have stimulated much activity in finding new treatments. This review summarizes the progress and setbacks of non-traditional ...approaches intent on circumventing bacterial drug resistance. These approaches include targeting virulence via toxin production and virulence factor secretion, impeding bacterial adhesion to host cells and biofilm formation, interrupting or inhibiting bacterial communication, and downregulating virulence. Other strategies include immune evasion, microbiome-modifying therapies, and the employment of phages as treatments or carriers. Finally, the prospects of nanoparticles, immunotherapy, antisense RNA, and drug-resistance-modulation approaches are discussed. The development of non-traditional treatments suffers similar challenges faced by developers of conventional antibiotics; however, most of these new strategies have additional and considerable hurdles before it can be shown that they are safe and efficacious for patient use. For the foreseeable future, it is likely that most of these treatments, if approved, will be used in combination with antibiotics.
The global crisis of drug resistance and few new antibiotics has inspired the investigation of non-traditional approaches to treating bacterial infections. This review discusses non-traditional strategies, including inhibition of bacterial colonization or infection of the host, immune evasion, and modification of the host microbiome, monoclonal antibodies, or viruses that infect bacteria.
To investigate the contribution of multidrug efflux pump systems of Salmonella enterica serovar Typhimurium to the formation of a competent biofilm.
Biofilm formation by a wild-type strain and 10 ...efflux mutant strains was quantified using crystal violet biofilm assays and visualized using scanning electron microscopy. Curli expression was investigated qualitatively and quantitatively by measuring binding of the dye Congo red to polymerized curli and by comparative RT-PCR.
All efflux mutants of Salmonella Typhimurium were compromised in their ability to form biofilms. Scanning electron microscopy images showed that the mutants were able to adhere to a surface but were unable to form a complex three-dimensional biofilm. Congo red assays demonstrated an inability of the efflux mutants to produce curli, a proteinaceous filament present on the cell surface and an essential component of the Salmonella biofilm extracellular matrix. Mutants expressed significantly less csgB or csgD than wild-type. Chemical inactivation of efflux in wild-type Salmonella Typhimurium with the efflux inhibitors (EIs) phenyl-arginine-β-naphthylamide, carbonyl cyanide m-chlorophenylhydrazone and chlorpromazine also repressed biofilm formation.
Our data demonstrates a link between all efflux systems of Salmonella Typhimurium and biofilm formation. Loss of functional efflux gives rise to a lack of curli expression. Biofilm formation was also inhibited by addition of a variety of EIs with differing mechanisms of action, suggesting a novel role for EIs as anti-biofilm compounds.
Infections arising from multidrug-resistant pathogenic bacteria are spreading rapidly throughout the world and threaten to become untreatable. The origins of resistance are numerous and complex, but ...one underlying factor is the capacity of bacteria to rapidly export drugs through the intrinsic activity of efflux pumps. In this Review, we describe recent advances that have increased our understanding of the structures and molecular mechanisms of multidrug efflux pumps in bacteria. Clinical and laboratory data indicate that efflux pumps function not only in the drug extrusion process but also in virulence and the adaptive responses that contribute to antimicrobial resistance during infection. The emerging picture of the structure, function and regulation of efflux pumps suggests opportunities for countering their activities.
Since 2000, most new discoveries and much preclinical research has been done in academia or Small Medium Enterprises but the lack of return of investment is a barrier to Big Pharma developing some of ...these inhibitors. ...working in collaboration with the IMI-funded project DRIVE-AB, the Review has suggested that the market be stimulated to develop and sell new antimicrobials by providing a reward system to those producing new treatments that will be of huge benefit to society even if they are not used. There has been a dearth of funding for antimicrobial-resistance research including for new treatments5,6 and public funding agencies did not fill the void when pharmaceutical companies started merging and divesting themselves of this area of activity. ...the Review recommends that a Global Innovation Fund for antimicrobial resistance should be established to pay for early stage research; the UK Prime Minister and the President of China have already indicated their intention to jointly contribute £100 million.
Abstract
Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate ...that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a ‘post-antibiotic era’. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry’s research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery.
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