oa Editorial [Hot Topic: Bacterial Virulence and the Development of Novel Antimicrobial Approaches (Guest Editor: Hongmin Sun)]

Infectious diseases have been one of the most critical threats to humans throughout evolution. Antibiotics have played a major role in controlling infectious diseases and increasing life span since the 1940s. Antibiotics target molecules involved in essential bacterial functions such as DNA, RNA, protein and lipid metabolism or cell wall formation. Wide use of antibiotics generates strong positive selective pressure for bacterial stains that are resistant to antibiotics, which arose shortly after the introduction of antibiotic use [1]. Over the years, nearly all major pathogens have developed resistance to antibiotics; stains have emerged that are resistant to most available antibiotics which pose a serious challenge to public healthcare systems worldwide. The emergence of multiply resistant strains is attributed to inappropriate and excessive use of antibiotics [2]. On the other hand, the development of novel antibiotics has been lagging [3, 4]. There is a thus an urgent need to develop new antimicrobial therapy which calls for more research on the mechanisms of bacterial pathogenicity that may lead to innovative alternative therapeutic approaches. In this special issue about bacterial virulence and the development of novel antimicrobial approaches, we have compiled seven reviews dealing with topics ranging from the mechanism of bacterial infection to the current status of antibiotic development. McArthur et al. describe the role of the major virulence factor streptokinase in Streptococcus pyogenes infection and discuss potential strategies to disrupt streptokinase's function for the treatment of invasive streptococcal infection. Streptococcus pyogenes is one of the most common human pathogens, causing various diseases from pharyngitis and mild skin infection to severe life threatening invasive diseases. S. pyogenes produces streptokinase to specifically activate human plasminogen, which plays a significant role in the pathogenicity of S. pyogenes infection. Based on the critical role of streptokinase in streptococcal virulence, novel therapeutical strategies are proposed to inhibit the interaction of streptokinase with plasminogen. Thomas and Lee provide a broader picture of S. pyogenes virulence, highlighting a number of major virulence factors of S. pyogenes. Potential therapeutic approaches dealing with streptococcal infection such as antimicrobial peptides, bacteriophage therapy and utilizing pathogenomics to identify potential therapeutic and vaccine targets are described. Gamez and Hammerschmidt highlight studies on Streptococcus pneumoniae adhesins and the potential of using adhesins as vaccine candidates. This review examines the pathogenic role of pneumococcal adhesins and their interactions with host proteins to evade host immune and cellular responses. These authors suggested that pneumococcal adhesins will be effective candidates for adhesin-based vaccines that may potentially prevent pneumococcal infections. Kline et al. describe type III secret systems (T3SS) and the potential of targeting it for antimicrobial therapy in Gram negative pathogens. T3SSs are Gram negative bacterial transmembrane protein systems that translocate virulence determinants or effector proteins into host cells. T3SS are well conserved among several Gram negative bacterial pathogens, making it feasible to identify compounds inhibiting the assembly or secretion process of T3SS in a broad range of Gram negative pathogens. This article listed efforts that identified inhibitors of T3SS by whole cell based high throughput screening and by specifically targeting certain proteins in the system by either in silico design or immuno-inhibition. The advantages and drawbacks of both approaches were discussed. Whole cell based high throughput screening will identify multiple broad spectrum inhibitors capable of inhibiting function of T3SS in multiple pathogens. Substantial challenges remain to identify the targets of the inhibitors of T3SS in such complicated systems and further optimization of leads. Target based screening on the other hand may prove to be of narrow spectrum and limited potency. Despite of the limitation of these approaches, the research summarized in this article illustrates the premise of some alternative approaches to target important virulence mechanisms of pathogens to counter the rise of antibiotic resistance. Robinson et al. assess the potential of targeting DNA replication for novel therapy. Due to the advances made in last decade in genome sequencing and other high throughput techniques, it is now feasible to assess the degree of conservation of bacterial DNA replication machinery between a wide range of bacteria in order to choose the best therapeutic targets. This article described our current understanding of bacterial DNA replication, progress in development of novel inhibitors of components of DNA replication machinery and opportunity to utilize genomic and structural knowledge to aid the design of potential inhibitors. However, significant hurdles still exist with this approach. Nonetheless, with an abundance of information of protein structure and protein-protein interaction, selective inhibitors may be developed in near future. The final two reviews describe the general landscape of searching for novel antibiotics. In spite of the obstacles for developing novel antibiotics, such as lack of economic incentives, the academic and commercial research communities continue contributing great effort to antibiotic research and development. Bulter and Cooper review screening strategies used to identify potential antibiotics. The article describes various screening methods for new antibiotics. In addition to well established traditional whole cell screening, high throughput screening combining with genomic information, screening with whole organism infection models, high content screening by analysing living cells and whole organisms, and antisense technology have all been implemented to advance antibacterial drug development. An interesting area for screening for antibiotics is targeting virulence mechanisms. These potential virulence inhibitors allow for non-selective mechanisms of control by inhibiting virulence instead of cell proliferation, resulting in a decreased selective pressure for evolution of antibiotic resistance. Lahiri et al. focus on structural and biophysical approaches in screening for hits and rational design of leads based on a deeper understanding of structure-activity relationships. Detail description of applying protein crystallography as well as solution based biophysical methods in selecting, characterizing and validating promising targets as well as identifying and optimizing lead compounds that inhibit their functions were provided and a number of case studies were listed. In summary, this special issue illustrates current studies searching for antimicrobial reagents and highlights the potential of utilizing our knowledge of virulence mechanism of bacterial pathogens to explore novel strategies to treat infectious disease, which is especially relevant given rising antibiotic resistance among major pathogens. Finally, I would like to thank Dr. Mark Walker (The University of Queensland) for his kind assistance in editing this special issue.