Therapeutic antibacterial drugs are considered among the safest of pharmaceuticals but this was not always the case. Indeed prior to the discovery of penicillin and, subsequently, other antibiotics, the safety profile of antibacterial drugs more closely resembled that of today's cytotoxic, chemotherapeutic agents used in oncology with narrow therapeutic windows and considerable side-effects. Today's antibiotics are, in fact, safe by design. Where agents have defined toxicities (e.g. photosensitivity induced by fluoroquinolones) they are usually class effects and, rather than 'idiosyncratic' are more frequently predictable based on pharmacokinetics and tissue distribution. As newer antibacterial drugs are being designed to be more 'pathogen specific' the expectation is that these future drugs will have even better safety profiles than today's therapeutics. The common perception of antibacterial drugs is that they are very safe, very useful and very important therapeutic agents, indeed the safety and tolerability of antibacterials are, in general are among the best of all prescribed drugs. This is not a matter of chance and it was not always the case. In 1908 Paul Ehrlich shared the Novel Prize for Medicine or Physiology (with Ilya Metchnikoff) for his work on immunotherapeutics (indeed the first Nobel Prize in that category went to Emil von Behring, also for immunotherapy) but Ehrlich was unhappy with the efficacy of immunotherapeutics as well as their safety (e.g. 'serum sickness'). He embarked on a bona fide medicinal chemistry/drug discovery campaign to find novel organic molecules based on arsenical compounds that were active against trypanosomes and spirochaetes. It should be noted that at the turn of the twentieth century mercury was still being used as treatment for syphilis, a bacterial infection caused by Treponema pallidum. Even today, mercury toxicity remains an important issue.The compound that Ehrlich's group eventually discovered, arsphenamine ('606') became known as Salvarsan and was both more effective and far safer than mercury treatment (not to mention less expensive) but was not without its own safety and tolerability issues (which are a subject of controversy even today) (Baumler, 1984). Eventually arsphenamine was supplanted by penicillin, where even a single, intramuscular dose was found to be effective in the early stages of the disease with a significantly better safety profile. It should be realized that today's antibacterial drugs are safe not as a matter of chance but by design; the result of decades of microbial research, the development of in vitro and animal models of infection, brute force science and inventive medicinal chemistry, and careful (as well as some careless) clinical research resulting in the successful treatment of hundreds of millions (if not billions) of people.

This chapter summarizes specific resistance mechanisms found in the staphylococci. When discussing resistance among the staphylococci, it is important to draw a distinction between community-acquired versus hospital-acquired (nosocomial) infections. Strains resistant to arsenicals and mercury were identified well before what is now known as the antibiotic era. From the genetic point of view, resistance falls into one of two classes: mutation of a bacterial gene or acquisition of a dedicated resistance gene from some other organism by some form of genetic exchange (transduction, conjugation, or transformation). In the history of antimicrobial chemotherapy, the most useful of antistaphylococcal agents have been the beta-lactam antibiotics, the prototype of which is penicillin. These agents, which include several structural classes, all contain one common structural feature: the beta-lactam ring. Rifampin, a member of the rifamycin class of antibiotics, inhibits transcription by attacking the beta-subunit of RNA polymerase. The fluoroquinolone antimicrobials are one of the few classes of antibacterial agents that are not based on a natural product. Sulfonamide resistance in the staphylococci, which arose soon after the introduction of the sulfa drugs, is chromosomally encoded (by the sulA gene) and is attributed to the overproduction of p-aminobenzoate. Mupirocin (formulated with the trade name Bactroban) has come into wide use as a topical agent for the treatment of gram-positive infections and more recently has been employed successfully to treat nasal carriers of methicillin-resistant S. aureus (MRSA), especially those in chronic care settings (e.g., nursing homes) and hospital staff.

The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable but can nevertheless be controlled, and it must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011. From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis.

For Francis Tally, both medicine and science were highly personal undertakings. Tally thought that emotional engagement was important in one's work and one's life, which were inseparable in his case. Indeed, Tally materially participated in no fewer than 4 programs that resulted in the approval and commercialization of novel antibiotics. These included piperacillin-tazobactam (which is currently the injectable antibiotic with the largest volume of sales worldwide) and daptomycin. This article focuses on the discovery and development of tigecycline.

In many areas of infectious diseases, there is a disparity between the intensity of medical need and the perceived commercial potential for the appropriate products. Wellknown examples include malaria and tuberculosis. For a variety of reasons, the same disparity is becoming reality for new antibacterial compounds which could address existing and emerging pathogens that are resistant to current antibiotics. In this chapter, we will review the history of antibiotic discovery and development to put everything else in an appropriate context. We will then explore the scientifi c challenges that have resulted in the paucity of novel antibacterials in today’s pipeline. Then we will examine the various factors that have coalesced to make antibacterials seem less commercially attractive for large companies. We will compare the situation in biotechnology and small pharmaceutical companies with that in large pharmaceutical companies. Finally, we will speculate on the future of antibacterial discovery and development given the emerging trends in science, in the marketplace, within the regulatory environment, and in the context of the pharmaceutical business.

Armed with whole genome sequences of multiple pathogenic bacteria, large collections of synthetic small molecules and natural product extracts, increasingly sophisticated laboratory automation, high throughput genetics, long lists of essential genes, high throughput screening, crystal structures, virtual (in silico) screening and phalanxes of medicinal chemists not a single antibacterial compound, derived by target based drug discovery, has entered clinical development. Despite a considerable industrial (and to a lesser extent academic) investment the futility in discovering new antibiotics has been palpable, especially during a time of increasingly widespread multidrug resistant strains of bacteria mainly in hospitals but apparently now spreading into the community. These failures may be more apparent than real but two things are becoming clear: we do not really understand bacterial resistance, especially as the ecological problem it is; nor do we appreciate what properties a truly “valid” molecular target should possess.

There has been a resurgent interest in the use of bacteriophages or their gene products to control bacterial pathogens as alternatives to currently used antibiotics. Clostridium perfringens is a gram-positive, spore-forming anaerobic bacterium that plays a significant role in human foodborne disease as well as non-foodborne human, animal, and avian diseases. Countries that have complied with the ban on antimicrobial growth promoters in feeds have reported increased incidences of C. perfringens-associated diseases in poultry. To address these issues, new antimicrobial agents, putative lysins encoded by the genomes of bacteriophages, are being identified in our laboratory. Poultry intestinal material, soil, sewage, and poultry processing drainage water were screened for virulent bacteriophages that could lyse C. perfringens and produce clear plaques in spot assays. Bacteriophages were isolated that had long noncontractile tails, members of the family Siphoviridae, and with short noncontractile tails, members of the family Podoviridae. Several bacteriophage genes were identified that encoded N-acetylmuramoyl-l-alanine amidases, lysozyme-endopeptidases, and a zinc carboxypeptidase domain that has not been previously reported in viral genomes. Putative phage lysin genes (ply) were cloned and expressed in Escherichia coli. The recombinant lysins were amidases capable of lysing both parental phage host strains of C. perfringens as well as other strains of the bacterium in spot and turbidity reduction assays, but did not lyse any clostridia beyond the species. Consequently, bacteriophage gene products could eventually be used to target bacterial pathogens, such as C. perfringens via a species-specific strategy, to control animal and human diseases without having deleterious effects on beneficial probiotic bacteria.

ABSTRACT The novel bicyclic penem inhibitor BLI-489 has demonstrated activity as an inhibitor of class A, C, and D β-lactamases. To determine the combination of piperacillin and BLI-489 to be used in susceptibility testing that would most accurately identify susceptible and resistant isolates, a predictor panel of β-lactamase-producing bacteria was utilized to determine the reliability of the combination of piperacillin-BLI-489 at a constant inhibitor concentration of 2 or 4 μg/ml and at ratios of 1:1, 2:1, 4:1, and 8:1. There were a number of strains that would be falsely reported as susceptible or intermediate if tested with the ratios of 1:1 and 2:1, whereas the constant concentration of 2 μg/ml of BLI-489 and the ratio of 8:1 had a tendency to overpredict resistance. Similar MICs were obtained with piperacillin-BLI-489 in a 4:1 ratio and when BLI-489 was held constant at 4 μg/ml. Based on these results, an in vitro testing methodology employing a constant concentration of 4 μg/ml BLI-489 was used to evaluate the combination of piperacillin-BLI-489 against a larger panel of recently identified clinical isolates. Approximately 55% of all of the enteric bacilli tested were nonsusceptible to piperacillin alone (MIC ≥ 32 μg/ml). However, 92% of these piperacillin nonsusceptible strains were inhibited by ≤16 μg/ml piperacillin-BLI-489; in contrast, only 66% were inhibited by ≤16 μg/ml piperacillin-tazobactam. The combination of piperacillin-BLI-489 also demonstrated improved activity compared to that of piperacillin-tazobactam against the problematic extended-spectrum β-lactamase- and AmpC-expressing strains.

The emergence of pathogenic bacteria resistant to virtually all available antibacterial agents at present has caused consternation among medical professionals, but has only intermittently raised concern among the public. This has led to a transient resurgence of interest in studying the mechanisms of resistance and in discovering and developing new antibacterial agents, but successes in the development of novel antibacterial agents have been few and far between. Although it has been known since the discovery of the tetracyclines that they are inhibitors of protein synthesis, there has been considerable recent progress on elucidating the mechanisms of action of the tetracyclines and in the enhanced understanding of the mechanisms of tetracycline resistance. In this case study, the authors discuss the discovery and development of a new class of antibacterials, which were derived from the tetracyclines, namely the glycylcyclines. This has resulted in the introduction of a new agent, tigecycline, to clinical practice. The glycylcyclines restore the antibacterial activity to levels of the earlier tetracyclines when they were first introduced, by overcoming the two major tetracycline-resistance mechanisms of efflux and ribosome protection, which promises to have a high degree of clinical utility.

Bacterial resistance to antimicrobial agents is a growing problem worldwide. Not only is issue compounded by the fact that there are fewer pharmaceutical companies conducting research to discover novel antimicrobials than in the past but development time lines have stretched so that a dozen years from discovery to the market is now the standard. Eleven antibacterial drugs in late stage clinical development are discussed. Whereas many of these may successfully deal with resistant strains of Gram-positive pathogens, there is very little in development to address the gorwing unmet medical need of multi-drug resistant Gram-negative infections.

The laws of natural selection dictate that bacteria will eventually develop resistance to practically any antibiotic.Selective pressure exerted by widespread antimicrobial use is a driving force in the development of antibiotic resistance.

ABSTRACT Despite its being a leading cause of nosocomal and community-acquired infections, surprisingly little is known about Staphylococcus aureus stress responses. In the current study, Affymetrix S. aureus GeneChips were used to define transcriptome changes in response to cold shock, heat shock, stringent, and SOS response-inducing conditions. Additionally, the RNA turnover properties of each response were measured. Each stress response induced distinct biological processes, subsets of virulence factors, and antibiotic determinants. The results were validated by real-time PCR and stress-mediated changes in antimicrobial agent susceptibility. Collectively, many S. aureus stress-responsive functions are conserved across bacteria, whereas others are unique to the organism. Sets of small stable RNA molecules with no open reading frames were also components of each response. Induction of the stringent, cold shock, and heat shock responses dramatically stabilized most mRNA species. Correlations between mRNA turnover properties and transcript titers suggest that S. aureus stress response-dependent alterations in transcript abundances can, in part, be attributed to alterations in RNA stability. This phenomenon was not observed within SOS-responsive cells.