In general, though, the outlook was more or less optimistic. Surprisingly, this is still true for T. The mortality rates due to multidrug-resistant bacterial infections are high. Estimated economic costs due to infections by multidrug-resistant bacteria in the EU result in extra healthcare costs and productivity losses of at least EUR 1. There are a number of excellent reviews elsewhere describing a variety of antibiotic resistance mechanisms and, within the frames of the bullet-target concept, these mechanisms can be classified as a target or bullet-related.
Targets can be: i protected by modification mutations making it insensitive to antibiotic action such as mutations in RNA polymerase conferring resistant to rifampin; ii modified by an enzyme such as methylation of an adenine residue in 23S rRNA making it insensitive to macrolides ; iii replaced for example, ribosomal protection proteins conferring resistance to tetracyclines ; and iv protected at cellular or population levels formation of a protective barrier by secretion, for example, of large amounts of exopolysaccharides.
Recent works in the area of antimicrobials and resistance suggest that not all interactions of bacteria with antibiotics can be explained within the frames of the classical bullet-target concept.
This well-established theory for the macro-organismal world seems also applicable to the microbial world, where a small number of antibiotic-resistant bacteria provide protection for the antibiotic sensitive cells, thus ensuring the survival of the whole population under the antibiotic assault.
Moreover, in complex biofilm consortia, the protection against antibiotics is offered to all community members, irrespectively of the kinship, which requires a conceptual framework operating at the system level. Thus the conceptual base of microbe—antibiotic interaction has been broadening beyond the bullet-target model to reflect the complexity of these interactions Davies et al.
The current state in the field of antimicrobials, resistance, and chemotherapy is certainly not limited to clinical microbiology as it was in the early years of the antibiotic era.
Thus, it is not a single grand challenge; it is rather a complex problem requiring concerted efforts of microbiologists, ecologists, health care specialists, educationalists, policy makers, legislative bodies, agricultural and pharmaceutical industry workers, and the public to deal with. In fact, this should be of everyone's concern, because, in the end, there is always a probability for any of us at some stage to get infected with a pathogen that is resistant to antibiotic treatment.
Moreover, even the behavioral patterns, such as hygienic habits or compliance with antibiotic treatment regimens, may have consequences that are not limited only to individual health issues but, on a larger scale, contribute to the interaction with the resistomes around us. In the following sections I will briefly touch upon some of the areas ranging from research to regulations to the cultural patterns that are important in dealing with the challenges of the antimicrobials, resistance, and therapy fields.
This strategy of modification of the existing antimicrobials was initiated and successfully implemented during the period, when the rate of discovery of novel drug classes suddenly dropped in the s, and the growing resistance problem enforced researchers to look into the possible modification of the existing arsenal that could confer improved activity, less sensitivity toward resistance mechanisms, and less toxicity Chopra et al.
Although this approach still successfully provides effective antimicrobials for the market, one of the lessons learned during this arms race is that sooner or later bacteria will acquire resistance to these modified versions as well through the horizontal acquisition of novel resistance mechanisms or rapid molecular evolution of the existing resistances to older antibiotics.
The antibiotic treatment choices for already existing or emerging hard-to-treat multidrug-resistant bacterial infections are limited, resulting in high morbidity and mortality rates.
Although there are some potential alternatives to antibiotic treatment such as passive immunization Keller and Stiehm, or phage therapy Levin and Bull, ; Monk et al. The vast majority of antimicrobial classes in use today have been isolated in the golden era of antibiotic discovery from a limited number of ecological niches and taxonomic groups, mainly from soil Actinomyces. What approaches could be taken to uncover the novel antimicrobials diversity that is potentially suitable for therapeutic applications?
Some possible approaches to tap the novel antimicrobial diversity is the exploration of ecological niches other than soil, such as the marine environment Hughes and Fenical, ; Rahman et al. The latter approach becomes dominant in the search for drugs aimed at the newly identified targets in a bacterial cell. Other strategies may include drugs engineered to possess dual target activities, such as a rifamycin—quinolone hybrid antibiotic, CBR Robertson et al. The vast majority of current antibiotics, even heavily modified, target the same cellular processes as their natural or synthetic predecessors.
With the extensive range of genomes sequenced, it becomes possible to implement the idea of a magic bullet in a more elaborate way, with essential targets defined much more precisely at the molecular level.
Successful implementations of this approach have already been demonstrated in the suppression of an important virulence factor, type III secretion system Negrea et al. The drugs initially designed for a different purpose may find application as antimicrobials. For example, BPH, a phosphonosulfonate, which was previously tested for cholesterol-lowering activity in humans as targeting the enzyme in cholesterol biosynthesis pathway, squalene synthase, is also inhibiting an important enzyme involved in Staphylococcus aureus virulence, dehydrosqualene synthase, and thus may be considered as a candidate drug to control MRSA Liu et al.
Other potential targets for intervention in bacterial metabolism include fatty acid biosynthesis Su and Honek, , cell division Lock and Harry, , biosynthesis of aminoacyl-tRNAs Schimmel et al. It should be noted that, moving along this route, we are cardinally departing from the previously defined classical structural divisions into antibiotic classes.
We are only at the beginning here, and not many antibacterial drugs with novel mechanisms of action have entered clinical trials yet, but even at this stage the majority of them do not belong to the previously defined antibiotic classes Devasahayam et al.
Also, the intervention strategies aimed not only at the targets but rather at biological networks may help to create new antibacterial therapies Kohanski et al. Combination therapy coupling antibiotics with an antibiotic-enhancing phage, for example, has demonstrated the potential to be a promising antimicrobial intervention Lu and Collins, The main problem we are facing with antibiotic therapy is that after a new antibiotic is introduced, resistance to it will, sooner or later, arise.
This scenario has been seen on multiple occasions, and thus there is a continuing race between the discovery and development of new antibiotics and the bacteria that will respond to this selective pressure by the emergence of resistance mechanisms. So how to protect the power of antibiotics and extend their lifespan?
There are many factors contributing to the emergence and dissemination of antibiotic resistance and, as mentioned before, the problems require a complex approach. A significant factor to consider apparently is the use of antibiotics by humans. Not surprisingly, the level of antibiotic-resistant infections strongly correlates with the level of antibiotic consumption Goossens et al.
There may be requests from patients to prescribe antibiotics when there is no need for them, as in the case of viral infections, and which should be explained to them. Indeed, the lack of knowledge about antibiotic resistance positively correlates with the higher prevalence of resistance Grigoryan et al. The important part is also to comply with the drug use regimen, which may be difficult in the case of infections requiring long-term therapy with multiple antibiotics as in the case of TB.
The contributing factor to the dissemination of antibiotic resistance, even in the case of absolute compliance, may be the practice of empirical prescription of antibiotics which accounts for the vast majority of prescriptions.
The development of express ABR profiling tests would be quite helpful in the initiation of the most efficient therapy available, avoiding the hurdles associated with a resistant pathogen. The situation is different in countries where the sales of antibiotics are inadequately regulated, and antibiotics are available without prescription. In the absence of regulation, the personal decisions on antibiotic purchase and use are governed by cultural and economic reasons Gartin et al.
Self-medication certainly lacks the attributes of a successful therapy, such as proper diagnosis, suitable antibiotic choice, correct usage, compliance, and treatment efficiency monitoring, thus contributing to the mounting resistance problem.
Domesticated animals also get infected and require antibiotic therapy. The agricultural use of antibiotics, however, is not limited exclusively to this use. Antibiotics are also used for the growth promotional and prophylactic purposes in food animals, as well as for a broader and less-targeted treatment in aquaculture and horticulture.
The experience of the Scandinavian countries, where the programs of optimal disease preventive management routines and proper use of antimicrobials, combined with the withdrawal of antibiotic growth promoters, were implemented in food animal production, is encouraging.
These measures resulted in reduction in the use of antimicrobials and prevented the creation of a relatively favorable situation for antimicrobial resistance Bengtsson and Wierup, With the ban of growth promoting antibiotics in , other EU countries have been implementing similar measures to limit the occurrence and dissemination of antibiotic resistance from agricultural sources.
Confirmatory to this suggestion are also the other therapeutic properties of antimicrobials, well beyond the initial range of use as anti-infective agents Griffin et al. Bacteria do not respect the boundaries of ecological compartments, and there is always a continuous flow by genetic information between different ecological compartments. Indeed, there is some evidence on the environmental origin of some clinically relevant resistance genes Wright, The recently emerged resistance to synthetic antibiotics of the quinolone class is mediated by the qnr genes that have been acquired from aquatic bacteria Poirel et al.
It was suggested that the original function of one of its homologs, MfpA, is providing DNA topological assistance when needed, and maintaining a condensed chromosome and preventing undesired topological changes during periods of replicative senescence Hegde et al.
Another important aspect is the release of antibiotics and the corresponding pre-selected and amplified antibiotic resistance gene pool from the human and animal ecological compartments back into the environment Chee-Sanford et al. What are the consequences of this? Does the resulting multidrug combination in the environment accelerate the evolution toward antimicrobial resistance Hegreness et al. What are the consequences of the presence of sublethal concentration antibiotics in the environment Kohanski et al.
What is the impact of the environmental stresses, such as, for example, the SOS response-inducing UV radiation, on the horizontal dissemination of antibiotic resistance genes Beaber et al.
Could the environment provide a broader playground for the mobile antibiotic resistance encoding elements to promote their own diversity Garriss et al. And what are the chances for antibiotic resistance genes to re-enter the human and animal food chain? There are pressing needs to answer these questions to build the broader strategies that would help to preserve the power of antibiotics. Albeit very brief, both on the global evolutionary and human history scales, the antibiotics era went through many ups and downs, providing us valuable lessons on many aspects of how the microbial world around us functions.
The discovery and use of antibiotics, antibiotic resistance markers, and mobile elements such plasmids were at the foundation of genetic engineering and molecular biology that eventually resulted in spectacular successes of the human genome and other sequencing projects.
These tools were also indispensable for shaping modern biotechnology ranging from the production of recombinant proteins to construction of entire metabolic pathways. Microorganisms, however, use the very same and probably some additional but still unidentified natural mechanisms to protect themselves against the massive antibiotic assaults continuously launched by the humankind from the time of discovery of antibiotics. Although the majority of infections were placed under control, this equilibrium in the arm race is fragile, since during the almost four billion years of evolution the microbial world has accumulated an enormous diversity of metabolic and protective mechanisms than can be mobilized in response to a strong selection.
We need to learn to be more precise in targeting the pathogens and limit the indiscriminate use of antimicrobials and other practices that accelerate the emergence of novel resistance mechanisms.
Investigation of the microbial world around us for potential mechanisms of antibiotic resistance and dissemination may help to design the early warning and preventive measures to sustain the efficacy of antimicrobials and chemotherapy. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
National Center for Biotechnology Information , U. Journal List Front Microbiol v. Front Microbiol. Published online Dec 8. Prepublished online Oct Rustam I. Author information Article notes Copyright and License information Disclaimer. Fleming isolated and grew the mould in pure culture. He found that P. After early trials in treating human wounds, collaborations with British pharmaceutical companies ensured that the mass production of penicillin the antibiotic chemical produced by P.
Following a fire in Boston, Massachusetts, USA, in which nearly people died, many survivors received skin grafts which are liable to infection by Staphylococcus. Treatment with penicillin was hugely successful, and the US government began supporting the mass production of the drug.
By D-Day in , penicillin was being widely used to treat troops for infections both in the field and in hospitals throughout Europe. By the end of World War II, penicillin was nicknamed 'the wonder drug' and had saved many lives. Billions of microscopic bacteria normally live on the skin, in the gut, and in our mouths and throats.
Most are harmless to humans, but some are pathogenic disease producing and can cause infections in the ears, throat, skin, and other parts of the body. In the pre-antibiotic era of the early s, people had no medicines against these common germs and as a result, human suffering was enormous.
For example,. Among those children who lived, most had severe and lasting disabilities, from deafness to mental retardation. Strep throat was at times a fatal disease, and ear infections sometimes spread from the ear to the brain, causing severe problems.
Other serious infections, from tuberculosis to pneumonia to whooping cough, were caused by aggressive bacteria that reproduced with extraordinary speed and led to serious illness and sometimes death. In the s, British scientist Alexander Fleming was working in his laboratory at St. In one of his experiments in , Fleming observed colonies of the common Staphylococcus aureus bacteria that had been worn down or killed by mold growing on the same plate or petri dish.
He determined that the mold made a substance that could dissolve the bacteria. He called this substance penicillin, named after the Penicillium mold that made it. Fleming and others conducted a series of experiments over the next 2 decades using penicillin removed from mold cultures that showed its ability to destroy infectious bacteria. They were able to make enough penicillin to begin testing it in animals and then humans. Starting in , they found that even low levels of penicillin cured very serious infections and saved many lives.
Drug companies were very interested in this discovery and started making penicillin for commercial purposes. It was used widely for treating soldiers during World War II, curing battlefield wound infections and pneumonia. By the mid- to late s, it became widely accessible for the general public.
Newspaper headlines hailed it as a miracle drug even though no medicine has ever really fit that description. With the success of penicillin, the race to produce other antibiotics began. At least million antibiotic prescriptions are written in the United States each year, many of them for children.
The success of antibiotics has been impressive. At the same time, however, excitement about them has been tempered by a phenomenon called antibiotic resistance. This is a problem that surfaced not long after the introduction of penicillin and now threatens the usefulness of these important medicines.
Almost from the beginning, doctors noted that in some cases, penicillin was not useful against certain strains of Staphylococcus aureus bacteria that causes skin infections. Since then, this problem of resistance has grown worse, involving other bacteria and antibiotics.
This is a public health concern. Increasingly, some serious infections have become more difficult to treat, forcing doctors to prescribe a second or even third antibiotic when the first treatment does not work. In light of this growing antibiotic resistance, many doctors have become much more careful in the way they prescribe these medicines.
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