http://www.mdpi.com/journal/antibiotics Latest open access articles published in Antibiotics at http://www.mdpi.com/journal/antibiotics http://www.mdpi.com/2079-6382/2/2/265 We investigated the effects of two novel copper-based inorganic formulations for their activity against 60 isolates of Helicobacter pylori (Hp). The two copper-based formulations were tested against three NCTC Helicobacter pylori isolates and 57 clinical strains isolated from the UK and Italy in time-kill assays. Both copper-based formulations were bio-cidal against all Helicobacter pylori strains tested reducing the viable count by 4–5 log within 2 h. These two copper-based anti-microbial agents deserve further study in relation to the treatment of H. pylori-related gastric disease. Antibiotics 2013-05-21 2 2 Article 10.3390/antibiotics2020265 265 273 2079-6382 2013-05-21 doi: 10.3390/antibiotics2020265 Ilaria Saracino Cristina Zaccaro Giovanna Re Dino Vaira John Holton http://www.mdpi.com/2079-6382/2/2/256 Regions Hospital started a multidisciplinary antibiotic stewardship program (ASP) in 1998. The program effectively shut down from 2002–2004 as key personnel departed and was then restarted but without the dedicated pharmacist and infectious diseases physician. Purchasing data (in dollars or dollars/patient/day) unadjusted for inflation served as a surrogate marker of antibiotic consumption. These data were reviewed monthly, quarterly, and yearly along with antibiotic susceptibility patterns on a semi-annual basis. Segmented regression analysis was use to compare restricted antibiotic purchases for performance periods of 1998–2001 (construction), 2002–2004 (de-construction), and 2005–2011 (reconstruction). After 4 years (1998–2001) of operation, a number of key participants of the ASP departed. For the following three years (2002–2004) the intensity and focus of the program floundered. This trend was averted when the program was revitalized in early 2005. The construction, deconstruction, and reconstruction of our ASP provided a unique opportunity to statistically examine the financial impact of our ASP or lack thereof in the same institution. We demonstrate a significant economic impact during ASP deconstruction and reconstruction. Antibiotics 2013-04-24 2 2 Article 10.3390/antibiotics2020256 256 264 2079-6382 2013-04-24 doi: 10.3390/antibiotics2020256 Mary Ullman Garry Parlier James Warren Noe Mateo Craig Harvey Christopher Sullivan Robert Bergsbaken Isaac Mitropoulos John Bosso John Rotschafer http://www.mdpi.com/2079-6382/2/2/237 The development of antibiotic resistance is usually associated with genetic changes, either to the acquisition of resistance genes, or to mutations in elements relevant for the activity of the antibiotic. However, in some situations resistance can be achieved without any genetic alteration; this is called phenotypic resistance. Non-inherited resistance is associated to specific processes such as growth in biofilms, a stationary growth phase or persistence. These situations might occur during infection but they are not usually considered in classical susceptibility tests at the clinical microbiology laboratories. Recent work has also shown that the susceptibility to antibiotics is highly dependent on the bacterial metabolism and that global metabolic regulators can modulate this phenotype. This modulation includes situations in which bacteria can be more resistant or more susceptible to antibiotics. Understanding these processes will thus help in establishing novel therapeutic approaches based on the actual susceptibility shown by bacteria during infection, which might differ from that determined in the laboratory. In this review, we discuss different examples of phenotypic resistance and the mechanisms that regulate the crosstalk between bacterial metabolism and the susceptibility to antibiotics. Finally, information on strategies currently under development for diminishing the phenotypic resistance to antibiotics of bacterial pathogens is presented. Antibiotics 2013-04-18 2 2 Review 10.3390/antibiotics2020237 237 255 2079-6382 2013-04-18 doi: 10.3390/antibiotics2020237 Fernando Corona Jose Martinez http://www.mdpi.com/2079-6382/2/2/217 Bacterial infections caused by antibiotic-resistant isolates have become a major health problem in recent years, since they are very difficult to treat, leading to an increase in morbidity and mortality. Fosfomycin is a broad-spectrum bactericidal antibiotic that inhibits cell wall biosynthesis in both Gram-negative and Gram-positive bacteria. This antibiotic has a unique mechanism of action and inhibits the initial step in peptidoglycan biosynthesis by blocking the enzyme, MurA. Fosfomycin has been used successfully for the treatment of urinary tract infections for a long time, but the increased emergence of antibiotic resistance has made fosfomycin a suitable candidate for the treatment of infections caused by multidrug-resistant pathogens, especially in combination with other therapeutic partners. The acquisition of fosfomycin resistance could threaten the reintroduction of this antibiotic for the treatment of bacterial infection. Here, we analyse the mechanism of action and molecular mechanisms for the development of fosfomycin resistance, including the modification of the antibiotic target, reduced antibiotic uptake and antibiotic inactivation. In addition, we describe the role of each pathway in clinical isolates. Antibiotics 2013-04-16 2 2 Review 10.3390/antibiotics2020217 217 236 2079-6382 2013-04-16 doi: 10.3390/antibiotics2020217 Alfredo Castañeda-García Jesús Blázquez Alexandro Rodríguez-Rojas http://www.mdpi.com/2079-6382/2/2/206 Seventy years after the introduction of antibiotic chemotherapy to treat tuberculosis, problems caused by drug-resistance in Mycobacterium tuberculosis have become greater than ever. The discovery and development of novel drugs and drug combination therapies will be critical to managing these problematic infections. However, to maintain effective therapy in the long-term and to avoid repeating the mistakes of the past, it is essential that we understand how resistance to antibiotics evolves in M. tuberculosis. Recent studies in genomics and genetics, employing both clinical isolates and model organisms, have revealed that resistance to the frontline anti-tuberculosis drug, rifampicin, is very strongly associated with the selection of fitness compensatory mutations in the different subunits of RNA polymerase. This mode of resistance evolution may also apply to other drugs, and knowledge of the rates and mechanisms could be used to design improved diagnostics and by tracking the evolution of infectious strains, to inform the optimization of therapies. Antibiotics 2013-04-03 2 2 Review 10.3390/antibiotics2020206 206 216 2079-6382 2013-04-03 doi: 10.3390/antibiotics2020206 Diarmaid Hughes Gerrit Brandis http://www.mdpi.com/2079-6382/2/2/191 Among the class of pollutants considered as ‘emerging contaminants’, antibiotic compounds including drugs used in medical therapy, biocides and disinfectants merit special consideration because their bioactivity in the environment is the result of their functional design. Antibiotics can alter the structure and function of microbial communities in the receiving environment and facilitate the development and spread of resistance in critical species of bacteria including pathogens. Methanogenesis, nitrogen transformation and sulphate reduction are among the key ecosystem processes performed by bacteria in nature that can also be affected by the impacts of environmental contamination by antibiotics. Together, the effects of the development of resistance in bacteria involved in maintaining overall ecosystem health and the development of resistance in human, animal and fish pathogens, make serious contributions to the risks associated with environmental pollution by antibiotics. In this brief review, we discuss the multiple impacts on human and ecosystem health of environmental contamination by antibiotic compounds. Antibiotics 2013-03-27 2 2 Review 10.3390/antibiotics2020191 191 205 2079-6382 2013-03-27 doi: 10.3390/antibiotics2020191 Patricia Keen David Patrick http://www.mdpi.com/2079-6382/2/2/182 The use of light-activated bactericidal agents—photobactericides—is suggested in local infection in order to conserve conventional antibacterials for more systemic disease. Local administration of a photobactericide such as methylene blue coupled with locally-targeted red light illumination ensures the production of non-specific reactive oxygen species and thus a rapid and localised antibacterial response, regardless of the conventional resistance status. To this end, the response of photobactericides to conventional resistance mechanisms, and their potential use in infection, is discussed. Antibiotics 2013-03-27 2 2 Opinion 10.3390/antibiotics2020182 182 190 2079-6382 2013-03-27 doi: 10.3390/antibiotics2020182 Mark Wainwright Leonard Amaral http://www.mdpi.com/2079-6382/2/1/163 Resistance-Nodulation-Division (RND) efflux pumps are one of the most important determinants of multidrug resistance (MDR) in Gram-negative bacteria. With an ever increasing number of Gram-negative clinical isolates exhibiting MDR phenotypes as a result of the activity of RND pumps, it is clear that the design of novel effective clinical strategies against such pathogens must be grounded in a better understanding of these pumps, including their physiological roles. To this end, recent evidence suggests that RND pumps play an important role in the virulence of Gram-negative pathogens. In this review, we discuss the important role RND efflux pumps play in different facets of virulence including colonization, evasion of host defense mechanisms, and biofilm formation. These studies provide key insights that may ultimately be applied towards strategies used in the design of effective therapeutics against MDR Gram negative bacterial pathogens. Antibiotics 2013-03-18 2 1 Review 10.3390/antibiotics2010163 163 181 2079-6382 2013-03-18 doi: 10.3390/antibiotics2010163 Dinesh Fernando Ayush Kumar http://www.mdpi.com/2079-6382/2/1/115 An environmental risk assessment (ERA) for the aquatic compartment in Europe from human use was developed for the old antibiotic Trimethoprim (TMP), comparing exposure and effects. The exposure assessment is based on European risk assessment default values on one hand and is refined with documented human use figures in Western Europe from IMS Health and measured removal in wastewater treatment on the other. The resulting predicted environmental concentrations (PECs) are compared with measured environmental concentrations (MECs) from Europe, based on a large dataset incorporating more than 1800 single MECs. On the effects side, available chronic ecotoxicity data from the literature were complemented by additional, new chronic results for fish and other organisms. Based on these data, chronic-based deterministic predicted no effect concentrations (PNECs) were derived as well as two different probabilistic PNEC ranges. The ERA compares surface water PECs and MECs with aquatic PNECs for TMP. Based on all the risk characterization ratios (PEC÷PNEC as well as MEC÷PNEC) and risk graphs, there is no significant risk to surface waters. Antibiotics 2013-03-18 2 1 Article 10.3390/antibiotics2010115 115 162 2079-6382 2013-03-18 doi: 10.3390/antibiotics2010115 Jürg Straub http://www.mdpi.com/2079-6382/2/1/100 Nowadays, the emergence and spread of antibiotic resistance have become an utmost medical and economical problem. It has also become evident that subinhibitory concentrations of antibiotics, which pollute all kind of terrestrial and aquatic environments, have a non-negligible effect on the evolution of antibiotic resistance in bacterial populations. Subinhibitory concentrations of antibiotics have a strong effect on mutation rates, horizontal gene transfer and biofilm formation, which may all contribute to the emergence and spread of antibiotic resistance. Therefore, the molecular mechanisms and the evolutionary pressures shaping the bacterial responses to subinhibitory concentrations of antibiotics merit to be extensively studied. Such knowledge is valuable for the development of strategies to increase the efficacy of antibiotic treatments and to extend the lifetime of antibiotics used in therapy by slowing down the emergence of antibiotic resistance. Antibiotics 2013-03-14 2 1 Review 10.3390/antibiotics2010100 100 114 2079-6382 2013-03-14 doi: 10.3390/antibiotics2010100 Luisa Laureti Ivan Matic Arnaud Gutierrez http://www.mdpi.com/2079-6382/2/1/83 Resistance mediated by efflux has been recognized in Staphylococcus aureus in the last few decades, although its clinical relevance has only been recognized recently. The existence of only a few studies on the individual and overall contribution of efflux to resistance phenotypes associated with the need of well-established methods to assess efflux activity in clinical isolates contributes greatly to the lack of solid knowledge of this mechanism in S. aureus. This study aims to provide information on approaches useful to the assessment and characterization of efflux activity, as well as contributing to our understanding of the role of efflux to phenotypes of antibiotic resistance and biocide tolerance in S. aureus clinical isolates. The results described show that efflux is an important contributor to fluoroquinolone resistance in S. aureus and suggest it as a major mechanism in the early stages of resistance development. We also show that efflux plays an important role on the reduced susceptibility to biocides in S. aureus, strengthening the importance of this long neglected resistance mechanism to the persistence and proliferation of antibiotic/biocide-resistant S. aureus in the hospital environment. Antibiotics 2013-03-13 2 1 Article 10.3390/antibiotics2010083 83 99 2079-6382 2013-03-13 doi: 10.3390/antibiotics2010083 Sofia Costa Elisabete Junqueira Cláudia Palma Miguel Viveiros José Melo-Cristino Leonard Amaral Isabel Couto http://www.mdpi.com/2079-6382/2/1/73 Acinetobacter baumannii may exhibit phenotypic heterogeneous growth under exposure to antibiotics. We investigated the in vitro characteristics of A. baumannii isolates grown heterogeneously in the presence of meropenem and their virulence evaluated in experimental infections treated with meropenem. Five clinical A. baumannii isolates and the respective heterogeneously grown subpopulations were tested by agar dilution minimum inhibitory concentration (MIC) testing, pulsed field gel electrophoresis (PFGE), population analysis using meropenem and growth curves. The virulence of isolates and the therapeutic efficacy of three meropenem dosing schemes was evaluated in a neutropenic murine thigh infection model. The clinical isolates were meropenem-susceptible (MICs 1 to 4 mg/liter) and exhibited three distinct PFGE patterns. In all clinical isolates, population analysis yielded heterogeneously grown colonies. After seven subcultures in antibiotic-free media, resistant MIC levels were retained in two isolates (heteroresistant), while three isolates were reversed to susceptible MICs (persisters). Clinical isolates and heterogeneous subpopulations had similar growth rates. The heterogeneously grown A. baumannii subpopulations had reduced virulence, killing considerably fewer animals than the respective clinical isolates without treatment. The meropenem treatment outcome was similar in infections caused by the clinical and the heterogeneous isolates, irrespective to their MICs. In vitro meropenem exposure induces phenotypic heterogeneous growth in A. baumannii. Compared with the parental clinical isolates, the heterogeneously grown subpopulations exhibited lower virulence, killing fewer mice and responding equally to meropenem treatment, despite their higher MICs. Antibiotics 2013-03-11 2 1 Article 10.3390/antibiotics2010073 73 82 2079-6382 2013-03-11 doi: 10.3390/antibiotics2010073 Evangelia Neou George Michail Athanassios Tsakris Spyros Pournaras http://www.mdpi.com/2079-6382/2/1/58 Phenothiazines have their primary effects on the plasma membranes of prokaryotes and eukaryotes. Among the components of the prokaryotic plasma membrane affected are efflux pumps, their energy sources and energy providing enzymes, such as ATPase, and genes that regulate and code for the permeability aspect of a bacterium. The response of multidrug and extensively drug resistant tuberculosis to phenothiazines shows an alternative therapy for the treatment of these dreaded diseases, which are claiming more and more lives every year throughout the world. Many phenothiazines have shown synergistic activity with several antibiotics thereby lowering the doses of antibiotics administered to patients suffering from specific bacterial infections. Trimeprazine is synergistic with trimethoprim. Flupenthixol (Fp) has been found to be synergistic with penicillin and chlorpromazine (CPZ); in addition, some antibiotics are also synergistic. Along with the antibacterial action described in this review, many phenothiazines possess plasmid curing activities, which render the bacterial carrier of the plasmid sensitive to antibiotics. Thus, simultaneous applications of a phenothiazine like TZ would not only act as an additional antibacterial agent but also would help to eliminate drug resistant plasmid from the infectious bacterial cells. Antibiotics 2013-02-18 2 1 Review 10.3390/antibiotics2010058 58 72 2079-6382 2013-02-18 doi: 10.3390/antibiotics2010058 Sujata Dastidar Jette Kristiansen Joseph Molnar Leonard Amaral http://www.mdpi.com/2079-6382/2/1/46 Due to the continuous release of antimicrobials into the environment, the aim of this study was to compare the frequency of detection of sulfamethazine, sulfamethoxypyridazine and trimethoprim in surface water collected from urban and rural areas in Northwestern Spain. A monitoring study was conducted with 314 river water samples analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry. The results indicated that 37% of the samples contained residues of at least one of the investigated antimicrobials, and every sampling site yielded positive samples. At sites located near the discharge points of wastewater treatment plants and near the collection point of a drinking-water treatment plant, more than 6% of the samples were positive for the presence of antimicrobial residues. Antibiotics 2013-02-07 2 1 Article 10.3390/antibiotics2010046 46 57 2079-6382 2013-02-07 doi: 10.3390/antibiotics2010046 Alejandra Iglesias Carolina Nebot Jose Miranda Beatriz Vázquez Carlos Abuín Alberto Cepeda http://www.mdpi.com/2079-6382/2/1/28 The paper focuses on recent achievements in the search for new chemical compounds able to inhibit multidrug resistance (MDR) mechanisms in Gram-positive pathogens. An analysis of the results of the search for new efflux pump inhibitors (EPIs) for Gram-positive bacteria, which have been performed over the last decade, indicates that almost all efforts are focused on the NorA (MFS) efflux pump in S. aureus. Considering the chemical structures of the NorA EPIs that have been identified, it can be observed that the most active agents belong to the families of compounds possessing conjugated double bonds, e.g., chalcones, piperine-like compounds, N-cinnamoylphenalkylamides or citral amide derivatives. Indole-, dihydronaphthyl-, 2-chloro-5-bromo-phenyl- or piperidine moieties seem to be profitable for the EPI properties, as well. These results, together with an increasing knowledge about a variety of efflux pumps that are involved in MDR of Gram-positive pathogens underline that further search for new EPIs should pay more attention to develop MDR efflux protein targets, including SMR, MATE, ABC or other members of the MFS family. Antibiotics 2013-02-05 2 1 Review 10.3390/antibiotics2010028 28 45 2079-6382 2013-02-05 doi: 10.3390/antibiotics2010028 Jadwiga Handzlik Anna Matys Katarzyna Kieć-Kononowicz http://www.mdpi.com/2079-6382/2/1/11 The yet uncharacterized membrane protein SA2056 belongs to the ubiquitous RND (Resistance-Nodulation-cell Division) family of transmembrane efflux transporters. The sa2056 gene is located downstream of femX, the gene encoding the essential, non-ribosomal peptidyl-transferase adding the first glycine in the staphylococcal cell wall pentaglycine interpeptide. Due to its proximity to and weak co-transcription with femX, we assumed that sa2056 may somehow be involved in peptidoglycan synthesis. Specific antibodies against SA2056 showed that this protein is expressed during growth and present in the membrane fraction of cell preparations. Using a bacterial two hybrid system, SA2056 was shown to interact (i) with itself, (ii) with FemB, which adds glycines 4 and 5 to the peptidoglycan interpeptide and (iii) with the essential penicillin binding proteins, PBP1 and PBP2, required for cell division and incorporation of the peptidoglycan into the cell wall. Unexpectedly, deletion of sa2056 led to no phenotype regarding growth, antibiotic resistances or cell morphology; nor did sa2056 deletion in combination with femB inactivation alter b-lactam and lysostaphin sensitivity and resistance, respectively, pointing to possible redundancy in the cell wall synthesis pathway. These results suggest an accessory role of SA2056 in S. aureus peptidoglycan synthesis, broadening the range of biological functions of RND proteins. Antibiotics 2013-01-22 2 1 Article 10.3390/antibiotics2010011 11 27 2079-6382 2013-01-22 doi: 10.3390/antibiotics2010011 Chantal Quiblier Agnieszka Luczak-Kadlubowska Esther Holdener Daniela Alborn Tanja Schneider Imke Wiedemann Mariana Pinho Hans-Georg Sahl Susanne Rohrer Brigitte Berger-Bächi Maria Senn http://www.mdpi.com/2079-6382/2/1/1 Background: In 14 randomized controlled studies to date, a procalcitonin (PCT)-based algorithm has been proven to markedly reduce the use of antibiotics along with an unimpaired high safety and low complication rates in patients with lower respiratory tract infections (LRTIs). However, compliance with the algorithm and safety out of controlled study conditions has not yet been sufficiently investigated. Methods: We performed a prospective international multicenter observational post-study surveillance of consecutive adults with community-acquired LRTI in 14 centers (Switzerland (n = 10), France (n = 3) and the United States (n = 1)). Results: Between September 2009 and November 2010, 1,759 patients were enrolled (median age 71; female sex 44.4%). 1,520 (86.4%) patients had a final diagnosis of LRTI (community-acquired pneumonia (CAP), 53.7%; acute exacerbation of chronic obstructive pulmonary disease (AECOPD), 17.1%; and acute bronchitis, 14.4%). Compliance with the PCT-guided therapy (overall 68.2%) was highest in patients with bronchitis (81.0% vs. AECOPD, 70.1%; CAP, 63.7%; p < 0.001), outpatients (86.1% vs. inpatients, 65.9%; p < 0.001) and algorithm-experienced centers (82.5% vs. algorithm-naive, 60.1%; p < 0.001) and showed significant geographical differences. The initial decision about the antibiotic therapy was based on PCT value in 72.4%. In another 8.6% of patients, antibiotics were administered despite low PCT values but according to predefined criteria. Thus, the algorithm was followed in 81.0% of patients. In a multivariable Cox hazard ratio model, longer antibiotic therapy duration was associated with algorithm-non-compliance, country, hospitalization, CAP vs. bronchitis, renal failure and algorithm-naïvety of the study center. In a multivariable logistic regression complications (death, empyema, ICU treatment, mechanical ventilation, relapse, and antibiotic-associated side effects) were significantly associated with increasing CURB65-Score, CAP vs. bronchitis, multilobar pneumonia, but not with algorithm-compliance. Discussion: Cultural and geographic differences in antibiotic prescribing affected the compliance with our PCT-guided algorithm. Efforts to reinforce compliance are needed. Antibiotic stewardship with PCT is possible, effective and safe without increasing the risk of complications in real-life conditions. Antibiotics 2013-01-22 2 1 Article 10.3390/antibiotics2010001 1 10 2079-6382 2013-01-22 doi: 10.3390/antibiotics2010001 Daniel Drozdov Frank Dusemund Beat Müller Werner Albrich http://www.mdpi.com/2079-6382/1/1/29 Helicobacter cinaedi causes infections, such as bacteremia, diarrhea and cellulitis in mainly immunocompromised patients. This pathogen is often problematic to analyze, and insufficient information is available, because it grows slowly and poorly in subculture under a microaerobic atmosphere. The first-choice therapy to eradicate H. cinaedi is antimicrobial chemotherapy; however, its use is linked to the development of resistance. Although we need to understand the antimicrobial resistance mechanisms of H. cinaedi, unfortunately, sufficient genetic tools for H. cinaedi have not yet been developed. In July 2012, the complete sequence of H. cinaedi strain PAGU 611, isolated from a case of human bacteremia, was announced. This strain possesses multidrug efflux systems, intrinsic antimicrobial resistance mechanisms and typical mutations in gyrA and the 23S rRNA gene, which are involved in acquired resistance to fluoroquinolones and macrolides, respectively. Here, we compare the organization and properties of the efflux systems of H. cinaedi with the multidrug efflux systems identified in other bacteria. Antibiotics 2012-11-21 1 1 Review 10.3390/antibiotics1010029 29 43 2079-6382 2012-11-21 doi: 10.3390/antibiotics1010029 Yuji Morita Junko Tomida Yoshiaki Kawamura http://www.mdpi.com/2079-6382/1/1/25 The synthesis of N-heterocyclic carbene (NHC) silver(I) acetate complexes with varying lipophilic benzyl-substituents at the 1 and 3 positions starting from 4,5-diphenylimidazole, opened a new class of antibiotic drug candidates. These NHC-silver(I) acetate derivatives exhibit interesting structural motifs in the solid state and proved to be soluble and stable in biological media. The leading candidate, SBC3, which was known to exhibit good antibacterial activity in preliminary Kirby-Bauer tests, was tested quantitatively using minimum inhibitory concentrations. NHC-silver(I) acetate complexes were found to have MIC values ranging from 20 to 3.13 μg/mL for a variety of Gram-positive, Gram-negative and mycobacteria tested. These values represent good antibiotic activities against potential pathogens when compared to clinically approved antibiotics. Most striking is the fact that SBC3 is active against methicillin-resistant Staphylococcus aureus with a MIC value of 12.5 μg/mL. Antibiotics 2012-11-20 1 1 Short Note 10.3390/antibiotics1010025 25 28 2079-6382 2012-11-20 doi: 10.3390/antibiotics1010025 Michael Sharkey James O'Gara Stephen Gordon Frauke Hackenberg Claire Healy Francesca Paradisi Siddappa Patil Bettina Schaible Matthias Tacke http://www.mdpi.com/2079-6382/1/1/17 It was shown that 5-chloro-8-hydroxyquinoline, an antituberculosis agent, gels aqueous alcohol solutions efficiently. Thermal stability and gel-to-sol transition temperature of 1% gel in CD3OD/D2O (2:1) was studied by 1H-NMR. Fibrous structures of four xerogels have been characterized by scanning electron microscope. Antibiotics 2012-09-19 1 1 Article 10.3390/antibiotics1010017 17 24 2079-6382 2012-09-19 doi: 10.3390/antibiotics1010017 Erkki Kolehmainen Hannu Salo Jukka Korpela http://www.mdpi.com/2079-6382/1/1/14 The miracle of antibiotics is hard to exaggerate. Each day, in every corner of the world, antibiotics improve, or could be improving outcomes in the septic neonate, the child with pneumonia, the new mother after a complicated delivery, the patient undergoing surgery, the nursing home resident with a urinary tract infection, the patient being treated of cancer, or the trauma patient on life support. The miracle also keeps our animals healthy for effective food production. But the miracle of these ‘wonder drugs’ is under threat and may be short lived: antimicrobial resistance is relentlessly increasing, especially for Gram negative organisms, prompting the oft expressed concern that we are plummeting head-long back into the pre-antibiotics era where clinicians and families once again will have to stand by and watch patients and loved ones die from once easily-treated infections. [...] Antibiotics 2012-06-14 1 1 Editorial 10.3390/antibiotics1010014 14 16 2079-6382 2012-06-14 doi: 10.3390/antibiotics1010014 Christopher C. Butler http://www.mdpi.com/2079-6382/1/1/1 By studying the literature about tetracyclines (TCs), it becomes clearly evident that TCs are very dynamic molecules. In some cases, their structure-activity-relationship (SAR) are well known, especially against bacteria, while against other targets, they are virtually unknown. In other diverse fields of research—such as neurology, oncology and virology—the utility and activity of the tetracyclines are being discovered and are also emerging as new technological fronts. The first aim of this paper is to classify the compounds already used in therapy and prepare the schematic structure that includes the next generation of TCs. The second aim of this work is to introduce a new framework for the classification of old and new TCs, using a medicinal chemistry approach to the structure of those drugs. A fully documented Structure-Activity-Relationship (SAR) is presented with the analysis data of antibacterial and nonantibacterial (antifungal, antiviral and anticancer) tetracyclines. The lipophilicity and the conformational interchangeability of the functional groups are employed to develop the rules for TC biological activity. Antibiotics 2012-06-12 1 1 Review 10.3390/antibiotics1010001 1 13 2079-6382 2012-06-12 doi: 10.3390/antibiotics1010001 Domenico Fuoco