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Biochemical Pharmacology (v.71, #7)

Editorial Advisory Board (pp. iii).

Editorial by S.J. Enna Editor-in-Chief; Michael Williams Editor (pp. 891-891).

Commensals upon us by M.N. Alekshun; S.B. Levy (pp. 893-900).

A battle to control and curtail bacterial infectious diseases is being waged in our hospitals and communities through antibiotic therapies and vaccines targeting specific species. But what effects do these interventions have on the epidemiology of infections caused by the organisms that are part of our natural microbial flora? Gram-positive and gram-negative bacteria appear as new disease agents from among commensal flora. These include vancomycin resistant enterococci (VRE), community-associated methicillin resistant Staphylococcus aureus (CA-MRSA), non-vaccine invasive serotypes of Streptococcus pneumoniae, new strains of non-type b Haemophilus influenzae and multi-drug resistant Escherichia coli. These examples illustrate how clinical improvements and widespread use and misuse of antibiotics have pushed evolution, allowing normally non-pathogenic strains to become infectious disease threats to human health.

Keywords: Commensal; Vaccine; Antibiotic resistance; MRSA; Infection; Immunity

Antibacterial drug discovery—Then, now and the genomics future by Richard L. Monaghan; John F. Barrett (pp. 901-909).

Drug discovery research in the area of infectious diseases, in particular that dealing with antibacterial/antibiotic susceptibility and resistance, is in a process of continuing evolution. Steeped in the history of the highly successful intervention with chemotherapeutic agents to treat human infections, the emergence of drug-resistant pathogens worldwide presents a serious unmet medical need, if not a pending catastrophe. Research in both academia and industry over the past 30 years using molecular biology, genetics and more recently – bacterial genomics – has assembled key enabling technologies to increase productivity and success rates in the discovery and development of novel antibacterial agents. However genomics is not limited only to antibacterial target selection but provides the opportunity to further understand key interactions in the use of antibacterial compounds as therapeutic agents (such as resistance emergence, susceptibility, efflux, interactions between compound and pathogen, etc.). Genomics also offers the potential for insights into: bacterial niche adaptation, host susceptibility, treatment regimens, antibiotic resistance, pharmacokinetics (e.g., host metabolism differences), safety and the microbial genesis of chronic diseases (e.g., gastric ulceration).

Keywords: Antibacterials; Antibiotics; Antibiotic synergy; Drug discovery; Genomics; Pathogen response – antibiotics; Resistance

Practical applications and feasibility of efflux pump inhibitors in the clinic—A vision for applied use by Olga Lomovskaya; Keith A. Bostian (pp. 910-918).

The world of antibiotic drug discovery and development is driven by the necessity to overcome antibiotic resistance in common Gram-positive and Gram-negative pathogens. However, the lack of Gram-negative activity among both recently approved antibiotics and compounds in the developmental pipeline is a general trend despite the fact that the plethora of covered drug targets are well-conserved across the bacterial kingdom. Such intrinsic resistance in Gram-negative bacteria is largely attributed to the activity of multidrug resistance (MDR) efflux pumps. Moreover, these pumps also play a significant role in acquired clinical resistance. Together, these considerations make efflux pumps attractive targets for inhibition in that the resultant efflux pump inhibitor (EPI)/antibiotic combination drug should exhibit increased potency, enhanced spectrum of activity and reduced propensity for acquired resistance. To date, at least one class of broad-spectrum EPI has been extensively characterized. While these efforts indicated a significant potential for developing small molecule inhibitors against efflux pumps, they did not result in a clinically useful compound. Stemming from the continued clinical pressure for novel approaches to combat drug resistant bacterial infections, second-generation programs have been initiated and show early promise to significantly improve the clinical usefulness of currently available and future antibiotics against otherwise recalcitrant Gram-negative infections. It is also apparent that some changes in regulatory decision-making regarding resistance would be very helpful in order to facilitate approval of agents aiming to reverse resistance and prevent its further development.

Keywords: Multidrug resistance; Efflux; RND transporters; EPIs; Pseudomonas; Fluoroquinolones

Natural products — The future scaffolds for novel antibiotics? by Mark S. Butler; Antony D. Buss (pp. 919-929).

Natural products have played a pivotal role in antibiotic drug discovery with most antibacterial drugs being derived from a natural product or natural product lead. However, the rapid onset of resistance to most antibacterial drugs diminishes their effectiveness considerably and necessitates a constant supply of new antibiotics for effective treatment of infections. The natural product templates of actinonin, pleuromutilin, ramoplanin and tiacumicin B, which are compounds undergoing clinical evaluation, represent templates not found in currently marketed antibacterial drugs. In addition, the new templates present in the recently discovered lead antibacterials arylomycin, GE23077, mannopeptimycin, muraymycin/caprazamycin, nocathiacin and ECO-0501, are discussed. Despite extensive efforts to identify antibiotic leads from molecular targets, only the peptide deformylase inhibitor LBM-415 is currently in clinical trials. It is proposed that new antibacterial assays which combine cell-based screening with molecular targets could offer better prospects for lead discovery.

Keywords: Natural product; Clinical trial; Template; Antibacterial; Antibiotic; Assay

Understanding the longevity of the β-lactam antibiotics and of antibiotic/β-lactamase inhibitor combinations by John D. Buynak (pp. 930-940).

Microbial resistance necessitates the search for new targets and new antibiotics. However, it is likely that resistance problems will eventually threaten these new products and it may, therefore, be instructive to review the successful employment of β-lactam antibiotic/β-lactamase inhibitor combinations to combat penicillin resistance. These combination drugs have proven successful for more than two decades, with inhibitor resistance still being relatively rare. The β-lactamase inhibitors are mechanism-based irreversible inactivators. The ability of the inhibitors to avoid resistance may be due to the structural similarities between the substrate and inhibitor.

Keywords: Antibiotic; β-Lactam; β-Lactamase; Resistance; Inhibitor; Mechanism

Dihydrofolate reductase inhibitors as antibacterial agents by Stephen Hawser; Sergio Lociuro; Khalid Islam (pp. 941-948).

Although only a few DHFR inhibitors have progressed as antibiotics to the market there is much renewed interest in the discovery and development of new generation DHFR inhibitors as antibacterial agents. This article describes the success in exploiting DHFR as a drugable target as exemplified by trimethoprim (TMP) and the development of several new diaminopyrimidines. Iclaprim, a recent example of a novel diaminopyrimidine currently in Phase III clinical trials, is also described together with several examples of anti-DHFR antibacterial compounds in pre-clinical development.

Efflux systems in bacterial pathogens: An opportunity for therapeutic intervention? An industry view by A. Simon Lynch (pp. 949-956).

The efflux systems of bacteria protect cells from antibiotics and biocides by actively transporting compounds out of the cytoplasm and/or periplasm and thereby limit their steady-state accumulation at their site(s) of action. The impact of efflux systems on the efficacy of antibiotics used in human medicine and animal husbandry is becoming increasingly apparent from the characterization of drug-resistant strains with altered drug efflux properties. In most instances, efflux-mediated antibiotic resistance arises from mutational events that result in their elevated expression and, in the case of efflux pumps with broad substrate specificity, can confer multi-drug resistance (MDR) to structurally unrelated antibiotics. Knowledge of the role of efflux systems in conferring antibiotic resistance has now been successfully exploited in the pharmaceutical industry and contributed, in part, to the development of new members of the macrolide and tetracycline classes of antibiotics that circumvent the efflux-based resistance mechanisms that have limited the clinical utility of their progenitors. The therapeutic utility of compounds that inhibit bacterial drug efflux pumps and therein potentiate the activity of a co-administered antibiotic agent remains to be validated in the clinical setting, but the approach holds promise for the future in improving the efficacy and/or extending the clinical utility of existing antibiotics. This review discusses the potential of further exploiting the knowledge of efflux-mediated antibiotic resistance in bacteria toward the discovery and development of new chemotherapeutic agents.

Keywords: Antibiotic efflux; Antibiotic resistance; Efflux pump; Transport protein; Efflux pump inhibitor; Antibiotic potentiating agent

Targeting the forgotten transglycosylases by Judy Halliday; Declan McKeveney; Craig Muldoon; Premraj Rajaratnam; Wim Meutermans (pp. 957-967).

Forty years ago, moenomycin was reported as a representative of a novel natural product class with strong antibacterial activity against Gram-positive organisms. Moenomycin was developed as an antimicrobial growth promoter in animal feeds. Mechanistically, moenomycin acts via inhibition of the transglycosylation process at the final stage of the peptidoglycan biosynthesis, in particular through binding directly to the transglycosylase enzymes, thereby preventing polymerisation of lipid II into linear peptidoglycan. Despite moenomycin's success, no developments of direct transglycosylase enzyme inhibitors were reported for over 30 years, probably due to the complexities and uncertainties surrounding the transglycosylation process, in particular the number of enzymes involved in the process and their specific roles. The development of better research tools and an improved understanding of the transglycosylation process, together with the increasing threat presented by multidrug-resistant bacteria, have led to a resurfacing of interest in targeting the forgotten transglycosylases. In addition, several new generation glycopeptides in clinical development inhibit the transglycosylation process, adding further value to the approach. In this paper, we summarise some of the developments in the area of transglycosylase inhibitors over the last 10 years.

Keywords: Transglycosylase inhibitors; PBP; Bacterial cell wall biosynthesis; Transglycosylation process; TG-domain

Glycopeptides: Update on an old successful antibiotic class by John L. Pace; Guang Yang (pp. 968-980).

The natural product glycopeptides vancomycin and teicoplanin have come to play a significant role in the therapy for Gram-positive bacterial infections. In particular vancomycin is the choice for empiric therapy of these infections primarily due to its activity against and the significance of methicillin-resistant Staphylococcus aureus. While high-level problematic glycopeptide resistance among enterococci was observed initially and continues to increase, the slow creep of vancomycin intermediate susceptibility and the fear of frank resistance among the staphylococci have precipitated increasing work leading to creation of new semisynthetic analogs. These new agents, including dalbavancin and telavancin, are within 1–2 years availability in the clinic. Interestingly, chemical modifications resulting in these second-generation analogs and additional characterization have revealed new mechanisms of antibacterial action, and plasticity regarding additional properties including pharmacokinetics for the drug candidates. The unique beneficial properties of the near term vancomycin replacements, semisynthesis of additional important analogs, and advances in metabolic engineering resulting in novel scaffolds signal a new era for the glycopeptide antibiotics.

Keywords: Glycopeptide; Antibiotic; Resistance; Delbavancin; Telavancin; Mechanism

The historical delivery of antibiotics from microbial natural products—Can history repeat? by Fernando Pel�ez (pp. 981-990).

Microbial natural products are the origin of most of the antibiotics on the market today. However, research in antibiotics and natural products has declined significantly during the last decade as a consequence of diverse factors, among which the lack of interest of industry in the field and the strong competition from collections of synthetic compounds as source of drug leads. As a consequence, there is an alarming scarcity of new antibiotic classes in the pipelines of the pharmaceutical industry. Still, microbial natural products remain the most promising source of novel antibiotics, although new approaches are required to improve the efficiency of the discovery process. The impact of microbial biodiversity, the influence of growth conditions on the production of secondary metabolites, the choice of the best approach at the screening step and the challenges faced during the isolation and identification of the active compounds are examined in this review as the critical factors contributing to success in the effort of antibiotic discovery from microbial natural products.

Keywords: Antibiotics; Natural products; Actinomycetes; Fungi; Screening; Lead discovery

Unmet medical needs in antibacterial therapy by Louis B. Rice (pp. 991-995).

The innate and evolutionary resourcefulness of bacterial pathogens virtually guarantees that there will always be important areas in which antimicrobial therapy can be improved. Current areas of need, or ones that are anticipated to be problematic in the near future include nosocomial infections caused by multi-resistant Gram-negative bacteria, where the variety and prevalence of multidrug efflux pumps provides a particular challenge to the designers of new drugs. In the community setting, the current prevalence of ampicillin and trimethoprim-sulfamethoxazole resistance, and the growing prevalence of fluoroquinolone resistance in Escherichia coli portend a need for new classes of oral agents to address this important need. On the Gram-positive side, the rapid increase in virulent community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections as a cause of pneumonia emphasizes the importance of developing more agents that are active against MRSA and that are effective for treating pneumonia. Finally, the importance of indwelling devices as a nidus for nosocomial infections emphasizes the need for effective agents for treating biofilm-associated device infection both inside and outside of the hospital.

Keywords: Antimicrobial agents; Efflux pumps; Porins; Biofilms; Resistance

Does the cell wall of bacteria remain a viable source of targets for novel antibiotics? by Lynn L. Silver (pp. 996-1005).

Whether the bacterial cell wall remains a viable source of novel antibacterials is addressed here by reviewing screen and design strategies for discovery of antibacterials with a focus on their output. Inhibitors for which antibacterial activity has been shown to be due to specific inhibition of a reaction (antibacterially validated inhibitors) are known for 8 of the 14 conserved essential steps of the pathway. Antibacterially validated enzyme inhibitors exist for six of these steps. The possible obstacles to finding validated inhibitors of the remaining enzymes are discussed and some strategies are suggested.

Keywords: Antibacterial agents; Antibacterial discovery; Antibiotics; Peptidoglycan synthesis; Mur; pathway; Cell wall antibiotics

Empirical antibacterial drug discovery—Foundation in natural products by Sheo B. Singh; John F. Barrett (pp. 1006-1015).

Natural products have been a rich source in providing leads for the development of drugs for the treatment of bacterial infections. However, beyond the discovery of the natural product, thienamycin and the synthetic lead, oxazolidinone in the 1970s, there has been a dearth of new compounds. This commentary provides an overview of current antibiotic leads and their mechanism of action, and highlights tools that can be applied to the discovery of new antibiotics.

Keywords: Natural products; Antibiotics; Fermentation; Mechanism-of-action; New targets; Empiric screening

Structure-based drug design meets the ribosome by Fran�ois Franceschi; Erin M. Duffy (pp. 1016-1025).

The high-resolution structures of the bacterial ribosomal subunits and those of their complexes with antibiotics have advanced significantly our understanding of small-molecule interactions with RNA. The wealth of RNA structural data generated by these structures has allowed computational chemists to employ a drug discovery paradigm focused on RNA-based targets. The structures also show how target-based resistance affects antibiotics acting at the level of the ribosome. Not only are the sites pinpointed where different classes of antibiotics inhibit protein synthesis, but their orientations, relative dispositions, and unique mechanisms of action are also revealed at the atomic level. Both the 30S and the 50S ribosomal subunits have been shown to be “targets of targets�?, offering several adjacent, functionally relevant binding pockets for antibiotics. It is the detailed knowledge of these validated locations, or ribofunctional loci, plus the mapping of the resistance hot-spots that allow the rational design of next-generation antibacterials.When the structural information is combined with a data-driven computational toolkit able to describe and predict molecular properties appropriate for bacterial cell penetration and drug-likeness, a structure-based drug design approach for novel antibacterials shows great promise.

Keywords: Antibacterials; Antibiotics; Structure-based drug design; Ribosomes; X-ray structure; Computational chemistry

Use of constraint-based modeling for the prediction and validation of antimicrobial targets by John D. Trawick; Christophe H. Schilling (pp. 1026-1035).

The overall process of antimicrobial drug discovery and development seems simple, to cure infectious disease by identifying suitable antibiotic drugs. However, this goal has been difficult to fulfill in recent years. Despite the promise of the high-throughput innovations sparked by the genomics revolution, discovery, and development of new antibiotics has lagged in recent years exacerbating the already serious problem of evolution of antibiotic resistance. Therefore, both new antimicrobials are desperately needed as are improvements to speed up or improve nearly all steps in the process of discovering novel antibiotics and bringing these to clinical use. Another product of the genomic revolution is the modeling of metabolism using computational methodologies. Genomic-scale networks of metabolic reactions based on stoichiometry, thermodynamics and other physico-chemical constraints that emulate microbial metabolism have been developed into valuable research tools in metabolic engineering and other fields. This constraint-based modeling is predictive in identifying critical reactions, metabolites, and genes in metabolism. This is extremely useful in determining and rationalizing cellular metabolic requirements. In turn, these methods can be used to predict potential metabolic targets for antimicrobial research especially if used to increase the confidence in prioritization of metabolic targets. The many different capacities of constraint-based modeling also enable prediction of cellular response to specific inhibitors such as antibiotics and this may, ultimately find a role in drug discovery and development. Herein, we describe the principles of metabolic modeling and how they might initially be applied to antimicrobial research.

Keywords: Constraint-based modeling; Metabolism; Antimicrobial research; In silico modeling; Essential gene; Flux balance analysis

Surveillance uncovers the smoking gun for resistance emergence by Jan Verhoef; Ad Fluit (pp. 1036-1041).

Today, antibiotic resistance is becoming a major healthcare concern. As global travel increases, more antibiotic-resistant bacteria will be disseminated from one country to another, thereby imposing a problem worldwide. Since the development of resistance is an evolutionary process, constant surveillance is needed to gain insight into the problem and surveillance studies needed to document the spread of antibiotic resistance.The basic objectives of surveillance studies in antimicrobial resistance are: to determine the level of resistance in a particular geographical area; to monitor changes in the level of resistance and make this information available to therapeutic policy-makers, as well as to detect new mechanisms of resistance for use as early warning signs; to study how such resistance develops, persists and spreads, and to monitor interventions.Although, surveillance provides the smoking gun for emergence of antibiotic resistance, improvement of the system is necessary and may be achieved through enhanced information technology and diagnostic tools.

Keywords: Antibiotic resistance; Surveillance studies; Methicillin-resistant; Staphylococcus aureus; Streptococcus pneumoniae; Hospital-acquired gram-negative rods; Mycobacterium tuberculosis

The evolution of peptide deformylase as a target: Contribution of biochemistry, genetics and genomics by Zhengyu Yuan; Richard J. White (pp. 1042-1047).

Although peptide deformylase (PDF, EC 3.5.1.27) was first described in 1968, the instability of enzyme preparations prevented it from being seriously considered as a target until this problem was finally solved in 1998. PDFs essentiality was first demonstrated in Escherichia coli in 1994. Genomic analyses have shown this enzyme to be present in all eubacteria. PDF homologs have also been found in eukaryotes including Homo sapiens. The function and relevance of the human chromosomal homolog to the safety of PDF inhibitors as therapeutic agents is not clear at this stage. Although there is considerable sequence variation between the different bacterial PDFs, there are three strongly conserved motifs that together constitute a critical metal binding site. The observation that PDF is a metalloenzyme has led to the design of inhibitors containing metal chelating pharmacophores. The most potent of these synthetic inhibitors are active against a range of clinically relevant respiratory tract pathogens in vitro and in vivo, including those resistant to current antibiotics. Mutants resistant to PDF inhibitors have been obtained in the laboratory; these resulted from mutations in the genes for transformylase (EC 2.1.2.9) or PDF. The mechanism involved and its frequency were pathogen-dependent. The two most advanced PDF inhibitor leads, which are both reverse hydroxamates, have progressed to phase 1 clinical trials and were well tolerated.

Keywords: Peptide deformylase; Peptide deformylase inhibitors; Antibacterial; Antibiotic resistance; Antimicrobial; Metalloenzyme

Crystallizing new approaches for antimicrobial drug discovery by Molly B. Schmid (pp. 1048-1056).

Over the past decade, the sequences of microbial genomes have accumulated, changing the strategies for the discovery of novel anti-infective agents. Targets have become plentiful, yet new antimicrobial agents have been slow to emerge from this effort. In part, this reflects the long discovery and development times needed to bring new drugs to market. In addition, bottlenecks have been revealed in the antimicrobial drug discovery process at the steps of identifying good leads, and optimizing those leads into drug candidates. The fruit of structural genomics may provide opportunities to overcome these bottlenecks and fill the antimicrobial pipeline, by using the tools of structure guided drug discovery (SGDD).

Keywords: Antimicrobial drug discovery; Structural genomics; Structure guided drug discovery; Antibiotics; Antibacterials

The role of pharmacodynamic research in the assessment and development of new antibacterial drugs by Philip D. Lister (pp. 1057-1065).

Antibacterial resistance continues to increase world wide, with some bacterial pathogens exhibiting resistance to virtually all available drugs. As the plague of antibacterial resistance continues to grow and create serious therapeutic problems, it is essential that the development of new antibacterial agents continue. Pharmacodynamic research plays an important role in the development of new antibacterial agents, as pharmacodynamic data can help define the clinical potential of a new drug and identify the strengths and weaknesses in comparison to other drugs already on the market. Furthermore, pharmacodynamic experiments can help focus the clinical phases of drug development by providing key information on the pharmacodynamic parameters that influence efficacy and the pharmacodynamic targets that should be achieved to optimize clinical success. Characterization of these pharmacodynamic properties for a new drug in development can help direct the design of the best dose and dosing strategy for clinical trials. This review will focus on the tools, methods, and strategies used to characterize the pharmacodynamics of antibacterial agents and aide in their development for clinical use.

Keywords: Antibacterial; Development; Pharmacodynamics; IVPM; Animal Models

Use of genomics to select antibacterial targets by Michael J. Pucci (pp. 1066-1072).

The problem of antibiotic resistance has eroded the usefulness of our arsenal of effective antibiotics. There is a need for new strategies to discover and develop new, effective drugs. The advent of the microbial genomics era has provided a wealth of information on a variety of microorganisms. This has allowed the identification and/or validation of a number of gene products that could serve as targets for the discovery of novel antibacterial agents. New genetic techniques and approaches have arisen in an attempt to exploit this newly available genomic data. Both random and targeted gene disruption efforts have proven effective in this process. Many of these methods would have been difficult to accomplish without DNA sequence and bioinformatics analyses. Several targets have been selected to further characterize and screen for inhibitors and one has yielded two clinical candidates.

Keywords: Genomics; Essentiality; Mutagenesis; Antibacterial; Bioinformatics; Antibiotic

The forgotten Gram-negative bacilli: What genetic determinants are telling us about the spread of antibiotic resistance by Thomas D. Gootz (pp. 1073-1084).

Gram-negative bacilli have become increasingly resistant to antibiotics over the past 2 decades due to selective pressure from the extensive use of antibiotics in the hospital and community. In addition, these bacteria have made optimum use of their innate genetic capabilities to extensively mutate structural and regulatory genes of antibiotic resistance factors, broadening their ability to modify or otherwise inactivate antibiotics in the cell. The great genetic plasticity of bacteria have permitted the transfer of resistance genes on plasmids and integrons between bacterial species allowing an unprecedented dissemination of genes leading to broad-spectrum resistance. As a result, many Gram-negative bacilli possess a complicated set of genes encoding efflux pumps, alterations in outer membrane lipopolysaccharides, regulation of porins and drug inactivating enzymes such as beta-lactamases, that diminish the clinical utility of today's antibiotics. The cross-species mobility of these resistance genes indicates that multidrug resistance will only increase in the future, impacting the efficacy of existing antimicrobials. This trend toward greater resistance comes at a time when very few new antibiotics have been identified capable of controlling such multi-antibiotic resistant pathogens. The continued dissemination of these resistance genes underscores the need for new classes of antibiotics that do not possess the liability of cross-resistance to existing classes of drugs and thereby having diminished potency against Gram-negative bacilli.

Keywords: Multidrug resistant; Klebsiella pneumoniae; ESBLs; Class 1 integrons; Carbapenemases; Porin mutations and deletions; Antibiotic efflux

Redefining penems by Axel Dalhoff; Nebojsa Janjic; Roger Echols (pp. 1085-1095).

The antimicrobial class of penems has the potential to address most of the relevant resistance issues associated with β-lactam antibiotics because of their exceptionally broad spectrum of antibacterial activity and their intrinsic stability against hydrolytic attack by many β-lactamases including ESBL and AmpC enzymes. The subclass of carbapenems covers the spectrum of hospital pathogens whereas the subclass of penems covers community pathogens. The only currently available penem, faropenem, has a low propensity for resistance development, β-lactamase induction and selection of carbapenem-resistant Pseudomonas aeruginosa. This makes it attractive for the treatment of community-acquired infections and for step-down or sequential therapy following carbapenem treatment without jeopardizing the activity of carbapenems or the entire β-lactam class in the hospital environment.

Keywords: Keyword; Penems

When will the genomics investment pay off for antibacterial discovery? by Scott D. Mills (pp. 1096-1102).

Effective solutions to antibacterial resistance are among the key unmet medical needs driving the antibacterial industry. A major thrust in a number of companies is the development of agents with new modes of action in order to bypass the increasing emergence of antibacterial resistance. However, few antibacterials marketed in the last 30 years have novel modes of action. Most recently, genomics and target-based screening technologies have been emphasized as a means to facilitate this and expedite the antibacterial discovery process. And although no new antibacterials have yet been marketed as result of these technologies, genomics has delivered well-validated novel bacterial targets as well as a host of genetic approaches to support the antibacterial discovery process. Likewise, high throughput screening technologies have delivered the capacity to perform robust screenings of large compound collections to identify target inhibitors for lead generation. One of the principal challenges still facing antibacterial discovery is to become proficient at optimizing target inhibitors into broad-spectrum antibacterials with appropriate in vivo properties. Genomics-based technologies clearly have the potential for additional application throughout the discovery process especially in the areas of structural biology and safety assessment.

Keywords: Antibacterial; Genomic; Bioinformatic; Target; Resistance; Screening

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Biochemical Pharmacology (v.71, #7)