An international multicenter study was undertaken to investigate the epidemiological dynamics of penicillin-resistant pneumococci. We compared the molecular epidemiological characteristics of 205 penicillin-resistant isolates originating from The Netherlands, Thailand, United States, Spain, Greece, Poland, Cuba, Germany, Finland, United Kingdom, South Africa, Hungary, Portugal, Croatia, and the Czech Republic. Eighty-four distinct restriction fragment end labeling (RFEL) types were observed. Twenty-eight genetic types were shared by two or more strains. Five genetic clusters consisted of strains originating from different countries, illustrating dissemination of penicillin-resistant pneumococci among countries. The strains displaying the two predominant RFEL types corresponding with the pandemic clones 23F and 9V were found in 10 and 6 different countries, respectively. This clearly demonstrates the pandemic behavior of these two clones. Twelve out of the 28 genetic clusters contained two or more serotypes. This finding indicates frequent horizontal transfer of capsular genes. Within distinct RFEL types, identical penicillin binding protein (PBP) genotypes were often observed, suggesting a high frequency of horizontal transfer of penicillin resistance genes. The most predominant PBP type was found in 15 distinct RFEL types, comprised 44% of the entire collection, and was observed in 11 countries. The vast majority of the strains belonging to the pandemic clones 23F and 9V shared this predominant PBP type. We hypothesize that the clones 23F and 9V are responsible for the worldwide increase of penicillin-resistance, because they serve as a genetic reservoir for susceptible pneumococci to acquire penicillin resistance.

The spread of multidrug-resistant Staphylococcus aureus strains, including methicillin-resistant S. aureus (MRSA), has shortened the useful life of anti-staphylococcal drugs enormously. Two approaches can be followed to address this problem: screening various sources for new leads for antibiotics or finding ways to disable the resistance mechanisms to existing antibiotics. Plants are resistant to most microorganisms, but despite extensive efforts to identify metabolites that are responsible for this resistance, no substantial progress has been made. Plants possibly use multiple strategies to deal with microorganisms that evolved over time. For this reason, we searched for plants that could potentiate the effects of known antibiotics. From 29 plant species tested, Cytisus striatus clearly showed such an activity and an NMR-based metabolomics study allowed the identification of compounds from the plant extracts that could act as antibiotic adjuvants. Isoflavonoids were found to potentiate the effect of ciprofloxacin and erythromycin against MRSA strains. For the structure-activity relationship (SAR), 22 isoflavonoids were assessed as antibiotic adjuvants. This study reveals a clear synergy between isoflavonoids and the tested antibiotics, showing their great potential for applications in the clinical therapy of infections with antibiotic-resistant microorganisms such as MRSA.

To investigate the molecular epidemiology of pneumococcal nasopharyngeal carriage in Hanoi, Vietnam, we studied 84 pneumococcal strains retrieved from children with upper respiratory tract infections. Serotypes 23F (32%), 19F (21%), 6B (13%), and 14 (10%) were found most often. A significant number of strains were antibiotic resistant. Fifty-two percent of the strains were (intermediate) resistant to penicillin, 87% were (intermediate) resistant to co-trimoxazole, 76% were resistant to tetracycline, 73% were resistant to erythromycin, and 39% were (intermediate) resistant to cefotaxime. Seventy-five percent were resistant to three or more classes of antibiotics. A high degree of genetic heterogeneity among the penicillin resistance genes was observed. In addition, the tetracycline resistance gene tet(M) and the erythromycin resistance gene erm(B) were predominantly observed among the isolates. Molecular analysis of the 84 isolates by restriction fragment end labeling (RFEL) revealed 35 distinct genotypes. Twelve of these genotypes represented a total of eight genetic clusters with 61 isolates (73%). The two largest clusters contained 24 and 12 isolates, and the isolates in those clusters were identical to the two internationally spreading multidrug-resistant clones Spain 23F-1 and Taiwan 19F-14, respectively. The remaining RFEL types were Vietnam specific, as they did not match the types in our reference collection of 193 distinct RFEL types from 16 countries. Furthermore, 57 of the 61 horizontally spreading isolates (93%) in the eight genetic clusters were covered by the seven-valent conjugate vaccine, whereas this vaccine covered only 43% of the isolates with unique genotypes. According to the serotype distribution of the nasopharyngeal pneumococcal isolates, this study suggests a high potential benefit of the seven-valent pneumococcal conjugate vaccine for children in Hanoi.

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Pneumococcal colonization was studied in 19 children monitored from birth through the age of 2 years. For this purpose, pneumococcal isolates were characterized by capsular typing, restriction fragment end labeling (RFEL), and penicillin-binding protein (PBP) genotyping. Fifty-eight isolates were collected and were found to belong to 10 capsular types, 31 RFEL types, and 7 PBP genotypes. Thirty-nine percent of the isolates had reduced susceptibility to penicillin. All seven highly resistant strains (MICs, >1 g/ml) were identical to the pandemic clone 23F. Children were culture positive between one and eight times at 13 scheduled visits. Although the infants were frequently recolonized with different strains, colonization with one particular strain often persisted for several months. Isolation of a previously detected capsular type was common, and the chromosomal homogeneity tended to be high when it occurred. Horizontal transfer of capsular genes between strains of different RFEL types was demonstrated in one child. The ecological advantage of transfer of capsular genes is unclear unless survival of the organism on a mucosal surface may be linked to immunoprotective pressure against particular capsular types.

Infectious diseases caused by multidrug-resistant (MDR) pathogens are spreading rapidly and are among the biggest threats to human health (1-4). A particular problem with drug discovery from microbial sources is the high frequency of rediscovery of known compounds, which necessitates new approaches to replenish the antimicrobial drug pipelines (5-7). To deal with the increasing antibiotic resistance, novel antibiotics are called for, or alternatively, the life spans of the current drugs must be prolonged by compounds counteracting resistance. Exemplary is amoxicillin-clavulanic acid (Augmentin), which is a combination of a ␤-lactam antibiotic (amoxicillin) and a ␤-lactamase inhibitor (clavulanic acid) (8).The cell wall and its biosynthetic machinery are a major target of the action of clinical antibiotics, including fosfomycin, bacitracin, cycloserine, ␤-lactam antibiotics (penicillins and cephalosporins), and glycopeptide antibiotics (vancomycin and teicoplanin) (9-11). Enterococci and many other Gram-positive pathogenic bacteria are resistant to a wide spectrum of antibiotics and can often be treated only with specific ␤-lactam antibiotics or with vancomycin (12-14). Vancomycin resistance was first discovered in the 1950s (15). Vancomycin resistance is exchanged between bacteria via movable elements such as transposon Tn1546, which is carried by many vancomycin-resistant enterococci (VRE) (16). The most common forms of transferable vancomycin resistance are the VanA-and VanB-type resistance, the expression of which is inducible by vancomycin. VanA-type strains are resistant to high levels of vancomycin as well as to another glycopeptide antibiotic, teicoplanin, while VanB-type strains show only inducible resistance to vancomycin but retain susceptibility to teicoplanin (17). While vancomycin resistance is most prevalent in enterococci (18), resistance has spread to methicillin-resistant Staphylococcus aureus (MRSA) (19). (15,23). The vancomycin resistance gene cluster provides resistance to both vancomycin and teicoplanin and is located on the genome of the vancomycin producer Amycolatopsis mediterranei (24,25) as well as that of other actinomycetes, including the model species Streptomyces coelicolor A3 (26, 27).Streptomycetes are Gram-positive soil bacteria with a complex multicellular life style (28-30). Streptomycetes are a major source of antibiotics and many other natural products of medical and biotechnological importance, such as anticancer, antifungal, or herbicidal compounds (31, 32). Due to the competitive environment of the soil, these microorganisms readily exchange genetic

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