Editorial overview: Antibiotic discovery: Feeding the pipeline or finding new pipes?

The United States GAIN (Generating Antibiotic Incentives Now) Act is a call to action for new antibiotic discovery and development that arises from a ground swell of concern over declining activity in this therapeutic area in the pharmaceutical sector. The GAIN Act aims to provide economic incentives for antibiotic drug discovery in the form of market exclusivity and accelerated drug approval processes. The legislation comes on the heels of nearly two decades of failure using the tools of modern drug discovery to find new antibiotic drugs. The lessons of failure are examined herein as are the prospects for a renewed effort in antibiotic drug discovery and development stimulated by new investments in both the public and private sector.

Antibiotics are proven as the most significant therapeutics in medical history. Antibiotic rapidly wiped out the infectious pathogens. It was a milestone achievement in medical history. But very soon, such landmark discovery was tarnished by antibiotic-resistant bacteria. They came into limelight just after the discovery of antibiotic, though penicillin discovery is followed by the discovery of numerous antibiotics and various are under trials, while some has to be approved by the FDA. Nevertheless, it was a achievement for the medical practitioners. Herein, in this chapter we have tried to encapsulate such a big voyage from discovery of antibiotics to current scenario of medicine.

OPINION article Front. Microbiol., 20 August 2013Sec. Antimicrobials, Resistance and Chemotherapy Volume 4 - 2013 | https://doi.org/10.3389/fmicb.2013.00240

Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an "apocalyptic" threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

Antibiotic discovery against Piscirickettsia salmonis using a combined in silico and in vitro approach

Antibiotics are essential components of current medical practice, but their effectiveness is being eroded by the increasing emergence of antimicrobial-resistant infections. At the same time, the rate of antibiotic discovery has slowed, and our future ability to treat infections is threatened. Among Christopher T. Walsh's many contributions to science was his early recognition of this threat and the potential of biosynthesis─genes and mechanisms─to contribute solutions. Here, we revisit a 2006 review by Walsh and co-workers that highlighted a major challenge in antibiotic natural product discovery: the daunting odds for identifying new naturally occurring antibiotics. The review described strategies to mitigate the odds challenge. These strategies have been used extensively by the natural product discovery community in the years since and have resulted in some promising discoveries. Despite these advances, the rarity of novel antibiotic natural products remains a barrier to discovery. We compare the challenge of discovering natural product antibiotics to the process of identifying new prime numbers, which are also challenging to find and an essential, if underappreciated, element of modern life. We propose that inclusion of filters for functional compounds early in the discovery pipeline is key to natural product antibiotic discovery, review some recent advances that enable this, and discuss some remaining challenges that need to be addressed to make antibiotic discovery sustainable in the future.

Antibiotic resistance is one of the growing concerns in healthcare settings. Most of the clinical and community (bacterial) strains have grown immune to almost all the available antibiotics. The discovery of new antibiotics or resurging of available antibiotics has failed to outcompete the growing resistance within the bacterial community. Thus, finding an alternative antibacterial modality to treat infectious diseases has become a significant objective among the scientific community around the globe. Phage therapy is one such an antibacterial therapy for the treatment of severe bacterial infections. The bacteriophages (or phage) are viruses that prey on bacteria for their multiplication and survival. Discovery of bacteriophage dates back to the early 1910s when Frederick W. Twort and Felix d'Herelle observed bacteriolytic activity. Before the discovery of antibiotics, phages were the choice of treatment against bacterial infections, but with the inconsistent research, phage therapy lost its importance in the therapeutics. With the emergence of antibiotic resistance, phage therapy and phage research has got a shape to revolutionize the growing bacterial infections. Phage therapy has shown promising results against severe bacterial infections in the circumstances where antibiotic treatment is ineffectual. This emergency has shed light on this forgotten therapy. This chapter will elucidate the history and fundamentals of phage biology and its significance in treating infectious diseases. With the special focus on advancements in phage research and their clinical outcomes which supports the use of phage therapy in humans. It also deals with the regulatory inputs required for phage therapy and the commercialization strategies undertaken by pharmaceuticals in the globalization of phage medicine. Besides, the authors would like to brief on the personalized phage therapy and their evolution from lab to bedside endpoints for treating the patients and other future perspectives that hold promise.

ConspectusBacterial infections pose an ongoing threat to global human health, an issue of growing urgency due to the emergence of resistance against many currently available antibiotics. Recently, the World Health Organization (WHO) launched a global appeal for the development of novel antibiotics to combat this issue. Ideal antibiotics should possess specific antibacterial effects, without causing resistance. However, the discovery of different antibiotics is lagging the development of drug-resistant bacteria. Many newly developed antibiotics not only are rapidly resisted by bacteria but also are ineffective against persistent bacteria embedded in biofilms and host cells. To tackle these challenges, innovative concepts and approaches are required for the discovery of novel antibacterial candidates.Agents for use against pathogenic bacteria were developed long before the discovery of antibiotics. For 3000 years, garlic has been considered an efficient antibacterial compound, utilized to prevent and treat bacterial infection worldwide, although the specific mechanisms remain unclear. Modern research shows that sulfur-containing chemicals are the primary active constituents of garlic and play key roles in its inherent antimicrobial activity, such as diallyl disulfide (DADS) and diallyl trisulfide (DATS). In contrast, inorganic sulfides for antibacterial use have not been deeply studied. It has been well-known that iron sulfides are an essential part of the geochemical and biological sulfur cycles. Both stable and metastable iron sulfides can be formed under abiotic sediment conditions and biotic process. In particular, certain bacteria species growth need iron sulfide as nutrient source or produce iron sulfide. In addition, iron sulfur clusters as special metastable iron sulfide take part in many important metabolic pathways in most organisms. These physicochemical and biological properties inspire us that iron sulfides are a type of valuable material for investigation and utilization.Below we will introduce a new antibacterial candidate based on iron sulfides, which kill bacteria via multiple mechanisms of action (MoAs). We will first discuss the types of iron sulfides with inherent antibacterial activity, i.e., metastable species that can release iron ions and polysulfides in aqua. The intrinsic properties of iron sulfides and released iron and polysulfides are analyzed in regard to antibacterial effects under different physiological conditions. In particular, ferrous ion–polysulfide synergized ferroptosis-like death is proposed to kill bacteria with broad spectrum and selectivity. In addition, the versatile MoAs enable metastable iron sulfides (mFeSs) to kill resistant bacteria, eradicate biofilms, and suppress intracellular persistent species without causing new drug resistance. Importantly, the efficient antibacterial properties have been validated in animal models bearing infections including wounds, pneumonia, caries, and bacterial vaginosis, demonstrating great translational potential. Lastly, we will summarize the challenges of iron sulfides, proposing a possible development direction in the future. Our studies on iron sulfides can serve as a paradigm for the design and discovery of antibacterial nanomaterials, which may contribute for the war against drug-resistant pathogenic bacteria.

Understanding the structural basis of antibacterial resistance may enable rational design principles that avoid and subvert that resistance, thus leading to the discovery of more effective antibiotics. In this review, we explore the use of crystal structures to guide new discovery of antibiotics that are effective against resistant organisms. Structures of efflux pumps bound to substrates and inhibitors have aided the design of compounds with lower affinity for the pump or inhibitors that more effectively block the pump. Structures of β-lactamase enzymes have revealed the mechanisms of action toward key carbapenems and structures of gyrase have aided the design of compounds that are less susceptible to point mutations.

Efflux pump inhibitors: new updates.

The discovery of antibiotics in the twentieth century made it possible to treat bacterial infections and revolutionized modern medicine. However, gradually, it is possible to perceive a decrease in the effectiveness of antimicrobial agents against pathogenic isolates, which, together with the low investment in the discovery and/or development of new antibiotics by large pharmaceutical companies since the 1960s, makes it increasingly difficult to treatment of infections caused by these microorganisms. The search for strategies capable of potentiating the effect of existing drugs through the development of new therapeutic approaches, which also have the potential to circumvent bacterial resistance to antibiotics, has become indispensable. In this context, metallic nanoparticles stand out, as they could be used to act synergistically with drugs. Thus, the objective of this review was to present the latest information on the synergistic activity of antibiotics with metallic nanoparticles, pointing out this association as a promising alternative for the preservation of bacterial sensitivity to these drugs. The different metallic nanoparticles can present different benefits in the treatment of bacterial infections, with this being able to potentiate the bacterial activity of antibiotics that are widely used in the clinic, being able to increase the susceptibility in multiresistant microorganisms. KEY POINTS: • Metallic nanoparticles increased the antimicrobial action of drugs; • Metallic nanoparticles compromise the action of bacterial efflux pumps; • Biofilm formation was inhibited after treatment with metallic nanoparticles.

Unlocking the synergistic potential of green metallic nanoparticles and antibiotics for antibacterial and wound healing activities.

Evolving medicinal chemistry strategies in antibiotic discovery

The widespread emergence of antibiotic-resistant bacteria and a lack of new pharmaceutical development have catalyzed a need for new and innovative approaches for antibiotic drug discovery. One bottleneck in antibiotic discovery is the lack of a rapid and comprehensive method to identify compound mode of action (MOA). Since a hallmark of antibiotic action is as an inhibitor of essential cellular targets and processes, we identify a set of 308 essential genes in the clinically important pathogen Staphylococcus aureus. A total of 446 strains differentially expressing these genes were constructed in a comprehensive platform of sensitized and resistant strains. A subset of strains allows either target underexpression or target overexpression by heterologous promoter replacements with a suite of tetracycline-regulatable promoters. A further subset of 236 antisense RNA-expressing clones allows knockdown expression of cognate targets. Knockdown expression confers selective antibiotic hypersensitivity, while target overexpression confers resistance. The antisense strains were configured into a TargetArray in which pools of sensitized strains were challenged in fitness tests. A rapid detection method measures strain responses toward antibiotics. The TargetArray antibiotic fitness test results show mechanistically informative biological fingerprints that allow MOA elucidation.

P.4.002 Serum factors as predictors of interferon-alpha (IFN-a)-induced depression