Ecology and Evolution as Targets: the Need for Novel Eco-Evo Drugs and Strategies To Fight Antibiotic Resistance Fernando Baquero, Teresa M. Coque and Fernando de la Cruz Antimicrob. Agents Chemother. 2011, 55(8):3649. DOI: Downloaded from 10.1128/AAC.00013-11. Published Ahead of Print 16 May 2011. Updated information and services can be found at: http://aac.asm.org/content/55/8/3649 http://aac.asm.org/ These include: REFERENCES This article cites 160 articles, 56 of which can be accessed free at: http://aac.asm.org/content/55/8/3649#ref-list-1 CONTENT ALERTS Receive: RSS Feeds, eTOCs, free email alerts (when new on January 3, 2013 by US EPA RTP/AWBERC Library articles cite this article), more» Information about commercial reprint orders: http://journals.asm.org/site/misc/reprints.xhtml To subscribe to to another ASM Journal go to: http://journals.asm.org/site/subscriptions/ ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2011, p. 3649–3660 Vol. 55, No. 8 0066-4804/11/$12.00 doi:10.1128/AAC.00013-11 Copyright © 2011, American Society for Microbiology. All Rights Reserved. MINIREVIEW Ecology and Evolution as Targets: the Need for Novel Eco-Evo Drugs and Strategies To Fight Antibiotic Resistanceᰔ† Downloaded from Fernando Baquero,1* Teresa M. Coque,1 and Fernando de la Cruz2 Department of Microbiology, Institute Ramo´n and Cajal for Health Research (IRYCIS), CIBER Research Network in Epidemiology and Public Health (CIBERESP), Ramo´n y Cajal University Hospital, Madrid,1 and Faculty of Medicine, Cantabria University, Santander,2 Spain In recent years, the explosive spread of antibiotic resistance determinants among pathogenic, commensal, and environmental bacteria has reached a global dimension. Classical measures trying to contain or slow locally the progress of antibiotic resistance in patients on the basis of better antibiotic prescribing policies have http://aac.asm.org/ clearly become insufficient at the global level. Urgent measures are needed to directly confront the processes influencing antibiotic resistance pollution in the microbiosphere. Recent interdisciplinary research indicates that new eco-evo drugs and strategies, which take ecology and evolution into account, have a promising role in resistance prevention, decontamination, and the eventual restoration of antibiotic susceptibility. This minire- view summarizes what is known and what should be further investigated to find drugs and strategies aiming to counteract the “four P’s,” penetration, promiscuity, plasticity, and persistence of rapidly spreading bacterial clones, mobile genetic elements, or resistance genes. The term “drug” is used in this eco-evo perspective as a tool to fight resistance that is able to prevent, cure, or decrease potential damage caused by antibiotic resistance, not necessarily only at the individual level (the patient) but also at the ecological and evolutionary on January 3, 2013 by US EPA RTP/AWBERC Library levels. This view offers a wealth of research opportunities for science and technology and also represents a large adaptive challenge for regulatory agencies and public health officers. Eco-evo drugs and interventions consti- tute a new avenue for research that might influence not only antibiotic resistance but the maintenance of a healthy interaction between humans and microbial systems in a rapidly changing biosphere. Insufficiency of current measures to control the emergence, and more recently, surveillance of hypermutable organisms selection, and spread of antimicrobial resistance. Antibiotic (85) and targeting controlling functions essential for infection resistance (AbR) is widespread in nature, and the goal of (26, 32, 61, 112). Controlling selection of AbR is a major eliminating all resistance genes is simply nonsense, as the nat- practical goal, which can be addressed again by the develop- ural function of most resistance genes has nothing to do with ment of novel anti-infective drugs and the appropriate use of AbR (91). Most probably, there is a huge “intrinsic resistome” antibiotics, avoiding low dosages able to select low-level mu- in bacterial organisms, composed of genes of varied phyloge- tations that can also serve as stepping stones for high-level netic origin that act as resistance genes only in the presence of resistance (9, 10, 45). Major efforts have been made to reduce the antibiotic (48, 60, 126). Cleansing nature of this gene pool general overconsumption of antimicrobial agents and thus is impossible. The most we can do is to try to control the limit the exposure of eventual resistant variants of pathogenic emergence, selection, and spread of AbR genes in bacterial and commensal bacteria to the high-intensity selective power organisms interacting with humans, animals, or plants (158). of these agents (53). Finally, a classical approach to avoid the The classical methods of controlling the emergence and spread spread of AbR is based on general hygiene and containment of AbR are based on the discovery of new antimicrobial agents (infection control) measures, decreasing contact between pa- (mostly in genocentric research) (52, 158), reduction of chronic tients contaminated (infected or carriers) with resistant bacte- antibiotic-promoted bacterial mutagenic stress, recombination, ria and noncontaminated patients (17, 18). and horizontal-transfer genetic events associated with low dos- Unfortunately, these measures are becoming increasingly ages (29, 82, 109, 143), suppression of phenotypic resistance insufficient in the current global landscape of AbR (19, 106, (34, 119, 154), use of combinations of drugs (16, 28, 44), in- 124). Avoiding the emergence of resistance in the individual cluding antagonistic drug pairs (92, 140), early intensive (front- patient is obviously important for the individual, but it has line) therapy, maintaining a low bacterial density (44, 47, 51), minimal effects in the community (123). The efficacy of classi- cal methods of controlling selection and spread is inversely proportional to the density and penetration (discussed below) * Corresponding author. Mailing address: Department of Microbi- (33) of resistant organisms and their mobile genetic elements ology, Ramo´n y Cajal University Hospital, Carretera de Colmenar, km in particular environments. Measures that might be successful 9.1, 28034 Madrid, Spain. Phone: 34-913368832. Fax: 34-913368809. in early stages of the development of resistance or in hospitals E-mail: [email protected]. ᰔ Published ahead of print on 16 May 2011. or countries with low rates of AbR have no value in areas † The authors have paid a fee to allow immediate free access to this where resistance is already an established biological phenom- article. enon (18, 115). Even in areas with low levels of AbR pollution, 3649 3650 MINIREVIEW ANTIMICROB.AGENTS CHEMOTHER. such as Sweden, recent studies have shown that a 2-year dis- ogy, which influences the whole evolution of microbial systems continuation of trimethoprim use had no influence at all on the (5, 21). Therefore, not only resistant bacteria should be con- Escherichia coli resistance rates (134). This was probably due sidered units of epidemiological surveillance of AbR, all other to the widespread distribution of trimethoprim resistance elements (pieces) able to shape the natural evolutionary his- genes (dfr) in replicons harboring other resistance determi- tory of AbR should also be considered (3, 121). Consequently, nants, thus ensuring coselection of dfr genes with other resis- all these biological-genetic elements, at any level of the hier- tance genes (20). Some regions of the world are densely pol- archy, should become targets for intervention against AbR. luted with AbR, while others remain clean (63, 137). In a Note that these genetic elements are frequently linked by co- global world, sooner or later, resistance originating in these operative interactions, so that altering the density of particular Downloaded from highly contaminated “sources of resistance” will invade envi- bacterial clones should have consequences on the selection and ronments that are still clean (137, 158). Some models suggest evolution of MGEs (74, 96, 110). that there is a threshold for this phenomenon. One of these Such a perspective indicates the need and possibility of using models shows that resistant organisms are constantly diluted “eco-evo” drugs, drugs acting not necessarily to cure the indi- and potentially extinguish in competition with constant immi- vidual patient (although this might happen for some antiviru- gration of susceptible bacteria in local environments, but such lence eco-evo drugs) but to “cure” specific environments from a trend might collapse due to the increase of resistant popu- AbR and to prevent or weaken the evolutionary possibilities lations (16). Moreover, the success of resistant organisms con- (the evolvability) of the biological elements involved in AbR. http://aac.asm.org/ tributes to the constant accumulation in the bacterial world of In other words, this perspective proposes to combat (decon- genetic platforms and vehicles able to efficiently recruit and taminate, de-evolve) resistance not only in infected patients spread novel resistance genes. AbR calls for more resistance but in a whole population composed of infected and nonin- and increases bacterial genetic evolvability in a phenomenon fected people alike, as occurs in hospitals, nurseries, or elderly described as “genetic capitalism” (7). At this time, resistance care facilities, as well as in general hot environments (“resis- might be reversible