Section Review Anti-infectives: New approaches to the treatment of vancomycin-resistant bacterial infections

Commercially available glycopeptides Vancomycin (V) and Teicoplanin (T) are drugs of choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (CNS), which are resistant to beta-lactams and almost all other first-line antibiotics. They are extensively used in the treatment of severe infections caused by multi-resistant Gram-positive pathogens including enterococci. Enterococcal infections have become a dramatic clinical problem since few antibacterial agents are efficacious against these refractory organisms and increasing resistance is rapidly eliminating the current options. The recent emergence and spread of resistance also to glycopeptides in VanA enterococci poses a serious threat for the future. Some strains of methicillin-resistant CNS have reduced susceptibility to T and occasionally to V. Currently, a major concern is the possibility already demonstrated at laboratory level, that high glycopeptide resistance could be transferred from enterococci to staphylococci. It follows that there is an urgent need for new more potent glycopeptides which combine improved activity against methicillin-resistant staphylococci with excellent activity against highly glycopeptide-resistant enterococci (GRE), or alternative drugs effective against these multi-resistant bacteria. This article describes the most recent findings and results achieved in this field with new glycopeptide derivatives and novel approaches based on modifications of the natural glycopeptide-core structure. Other promising investigational drugs potentially useful for overcoming the serious therapeutic problem of glycopeptide-resistant bacterial infections are also reviewed.     

When will the genomics investment pay off for antibacterial discovery?

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.     

New agents in development for the treatment of bacterial infections

New antibacterial agents to treat infections caused by antibiotic-susceptible and antibiotic-resistant pathogens are in various stages of clinical development. In this review are compounds with demonstrated activity against methicillin-resistant staphylococci including investigational cephalosporins, carbapenems, and a new tetracycline, as well as glycopeptides effective against vancomycin-resistant enterococci (VRE), and fluoroquinolones with improved potency against respiratory pathogens and multidrug-resistant Gram-positive bacteria. Although most recent progress has occurred in the identification of agents for Gram-positive infections, broad-spectrum carbapenems are described for the treatment of multidrug-resistant Gram-negative pathogens. Also discussed are agents with mechanisms of action other than inhibition of protein synthesis, penicillin-binding proteins, and DNA topoisomerases; among these are inhibitors of bacterial fatty acid biosynthesis, peptidoglycan synthesis, and dihydrofolate reductase.     

Therapies in development for community-acquired pneumonia

The current use of antimicrobials has become more complex due to the extensive emergence of antibiotic resistance. The single most important approach in resistance control is probably the judicious use of chemotherapeutic agents. New agents that may be of use in the treatment of community-acquired pneumonia are currently in development. Antimicrobials can be grouped according to their mechanism of action. These include protein synthesis inhibitors (ketolides, oxazolidinones, streptogramins and glycylcyclines), nucleic acid synthesis inhibitors (fluoroquinolones), peptidoglycan synthesis inhibitors (beta-lactams and glycopeptides) and agents interfering with membrane function (cationic peptides and lipopeptides). Among those agents under development, only the oxazolidinones, the cationic peptides and the lipopeptide antibiotics can be truly regarded as structurally novel inhibitors as the other agents are analogues of existing compounds which have been in clinical use for many years.     

Glycopeptide antibiotics and their novel semi-synthetic derivatives

Glycopeptide antibiotics, vancomycin and teicoplanin, inhibit cell wall synthesis in Gram-positive bacteria by interacting with peptidoglycan D-Ala-D-Ala peptide stem termini of the pentapeptide side chains of the peptidoglycan precursors. In glycopeptide-resistant bacteria, multiresistance poses major therapeutic problems. New potent antibacterial agents are needed to combat these resistance problems, resulting in the explosion of novel glycopeptides in recent years. The glycosylation patterns of glycopeptides and the chemical modifications of the glycosyl moieties greatly influence their antibiotic activity, and certain combinations have resulted in highly active new compounds. Considerable efforts have been made to produce semisynthetic glycopeptides with improved pharmacokinetic and pharmacodynamic properties and activity towards resistant strains. This review provides an overview of the chemistry, the antimicrobial activity, the pharmacokinetics and the toxicology of teicoplanin and other glycopeptide antibiotic derivatives.     

Novel FabH inhibitors: a patent and article literature review (2000 – 2012)

Introduction: The traditional antimicrobial chemotherapy drugs play their effects mostly via bacterial interference with in vivo amino acids, nucleotides, amino sugars and other small molecule synthesis, or interfering the biochemical processes of these small molecules to synthesize nucleic acids, peptidoglycan and other biological macromolecules. In recent years, enzymes with single function in bacterial fatty acid synthetase system have become the genome-driven novel antibacterial drug targets. Among inhibitors of these targets, FabH inhibitors are distinguished, for their target is different from that of existing antibiotics. Therefore, discovery of FabH inhibitors might be a potential orientation to overcome bacterial resistance.

Areas covered: This review summarized new patents and articles published on FabH inhibitors from 2000 to 2012.

Expert opinion: The review gives a brief understanding about the background and development in the area of FabH inhibitors that aims to solve the bacterial resistance problem. This review puts emphasis on some typical small molecules, which participate in the process of FabH inhibition. Overall, the research scopes of antibacterial agents are getting broad. Fatty acid synthase (FAS) pathway has been proved to be a promising target for the therapy. However, claim of novel antibacterial agents with more active and higher specificity is still continued.     

Phosphinate inhibitors of UDP-N-acetylmuramoyl-L-alanyl-D-glutamate: L-lysine ligase (MurE)

The increasing emergence of pathogenic bacterial strains with high resistance to antibiotic therapy has created an urgent need for the development of new antibacterial agents that are directed towards novel targets. We have focused our attention on the Mur ligases (MurC-F), which catalyze the early steps of bacterial peptidoglycan biosynthesis, and which to date represent under-exploited targets for antibacterial drug design. We show that some of our phosphinate inhibitors of UDP-N-acetylmuramoyl-L-alanyl:D-glutamate ligase (MurD) also inhibits UDP-N-acetylmuramoyl-L-alanyl-D-glutamate:L-lysine ligase (MurE). To obtain new information on their structure-activity relationships, three new, structurally related phosphinates were synthesized and evaluated for inhibition of MurD and MurE.     

Computational Methods to Identify New Antibacterial Targets

The development of resistance to all current antibiotics in the clinic means there is an urgent unmet need for novel antibacterial agents with new modes of action. One of the best ways of finding these is to identify new essential bacterial enzymes to target. The advent of a number of in silico tools has aided classical methods of discovering new antibacterial targets, and these programs are the subject of this review. Many of these tools apply a cheminformatic approach, utilizing the structural information of either ligand or protein, chemogenomic databases, and docking algorithms to identify putative antibacterial targets. Considering the wealth of potential drug targets identified from genomic research, these approaches are perfectly placed to mine this rich resource and complement drug discovery programs.     

Advances in the discovery of novel antibacterial agents during the year 2002

The development of bacterial resistance is a significant problem in the treatment of infection, and the importance of research directed toward the discovery of novel agents to treat infections cannot be underestimated. In the past, discovery programs have focused on modification of natural products or existing classes of marketed antibacterial agents. A significant period of time lapsed between the introduction of the nalidixic acid-based quinolones and the next novel antibacterial agent (Zyvox). However, the advent of the "genomics era" has provided a wealth of new targets that afford the opportunity to discover novel antibacterial agents. This review reports on the state of antibacterial research directed toward the development of novel antibacterial agents with novel mechanisms of action for the calendar year, 2002. While variations on existing drug classes continue to appear, we have chosen to limit our discussion to novel classes of antibacterial agents which have not yet been marketed.     

Multidrug-resistant Streptococcus pneumoniae infections: current and future therapeutic options

Antibacterial resistance in Streptococcus pneumoniae is increasing worldwide, affecting principally beta-lactams and macrolides (prevalence ranging between approximately 1% and 90% depending on the geographical area). Fluoroquinolone resistance has also started to emerge in countries with high level of antibacterial resistance and consumption. Of more concern, 40% of pneumococci display multi-drug resistant phenotypes, again with highly variable prevalence among countries. Infections caused by resistant pneumococci can still be treated using first-line antibacterials (beta-lactams), provided the dosage is optimised to cover less susceptible strains. Macrolides can no longer be used as monotherapy, but are combined with beta-lactams to cover intracellular bacteria. Ketolides could be an alternative, but toxicity issues have recently restricted the use of telithromycin in the US. The so-called respiratory fluoroquinolones offer the advantages of easy administration and a spectrum covering extracellular and intracellular pathogens. However, their broad spectrum raises questions regarding the global risk of resistance selection and their safety profile is far from optimal for wide use in the community. For multi-drug resistant pneumococci, ketolides and fluoroquinolones could be considered. A large number of drugs with activity against these multi-drug resistant strains (cephalosporins, carbapenems, glycopeptides, lipopeptides, ketolides, lincosamides, oxazolidinones, glycylcyclines, quinolones, deformylase inhibitors) are currently in development. Most of them are only new derivatives in existing classes, with improved intrinsic activity or lower susceptibility to resistance mechanisms. Except for the new fluoroquinolones, these agents are also primarily targeted towards methicillin-resistant Staphylococcus aureus infections; therefore, demonstration of their clinical efficacy in the management of pneumococcal infections is still awaited.     

The future challenges facing the development of new antimicrobial drugs

The emergence of resistance to antibacterial agents is a pressing concern for human health. New drugs to combat this problem are therefore in great demand, but as past experience indicates, the time for resistance to new drugs to develop is often short. Conventionally, antibacterial drugs have been developed on the basis of their ability to inhibit bacterial multiplication, and this remains at the core of most approaches to discover new antibacterial drugs. Here, we focus primarily on an alternative novel strategy for antibacterial drug development that could potentially alleviate the current situation of drug resistance--targeting non-multiplying latent bacteria, which prolong the duration of antimicrobial chemotherapy and so might increase the rate of development of resistance.     

Emerging bacterial enzyme targets

The treatment of bacterial infections is increasingly complicated by the ability of bacteria to develop resistance to antimicrobial agents, as well as by the emergence of new pathogens with the potential for rapid global spread. Thus, there is a critical need for novel antibacterial agents and new strategies to advance the drug discovery process. In the post-genomic era, comparative genomics, functional genomics and proteomics will play important roles in identifying new enzyme targets for the discovery of novel antibacterial agents. This review will discuss bacterial enzyme targets, specifically focusing on enzymes involved in fatty acid and cell wall biosynthesis.     

New antimicrobial agents on the horizon

Antibiotic resistance issues necessitate the continued discovery and development of new antibacterial agents. Efforts are ongoing in two approaches to find new compounds that are effective against antibiotic-resistant pathogens. These efforts involve modification of existing classes including fluoroquinolones, tetracyclines, aminoglycosides, and β-lactams and identification of inhibitors against previously unexploited antibacterial targets. Examples of both approaches are described here with emphasis on compounds in late pre-clinical or clinical stages of development.     

Inhibition of transglycosylation involved in bacterial peptidoglycan synthesis

The continuing spectre of resistance to antimicrobial agents has driven a sustained search for new agents that possess activity on drug resistant bacteria. Although several paths are available to reach this goal, the most generalized would be the discovery and clinical development of an agent that acts on a new target which has not yet experienced selective pressure in the clinical setting. Such a target should be essential to the growth and survival of bacteria, and sufficiently different from, or better still non-existent in, the human host. The transglycosylation reaction that polymerizes biochemical intermediates into peptidoglycan qualifies as such a target. This biochemical system accepts the basic unit N-acetylglucosamine-beta-1, 4-N-acetyl-muramyl-pentapeptide-pyrophosphoryl-undecaprenol (lipid II), and leads to polymerization of the N-acetylglucosamine -beta-1, 4-N-acetyl-muramyl-pentapeptide segment into peptidoglycan. Approaches to targeting this reaction include modification of known glycolipid and glycopeptide natural product antibiotics. The synthesis and antibacterial activity of synthetic analogs of moenomycin having novel antibacterial activities not present in the parent structure will be presented, together with the combinatorial chemistry and assay systems leading to their discovery. Likewise, we will discuss chemical modifications to specific glycopeptide antibiotics that have extended their spectrum to include vancomycin resistant enterococci that substitute D-alanyl-D-lactate for D-alanyl-D-alanine in their peptidoglycan. Two differing theories, one positing the generation of high affinity, specific binding to D-alanyl-D-lactate via glycopeptide dimerization and/or membrane anchoring, and the other supporting direct targeting of the modified glycopeptide to the transglycosylation complex, seek to explain the mechanism of action on vancomycin resistant enterococci. Biochemical evidence in support of these two theories will be discussed.     

Bifunctional penicillin-binding proteins: focus on the glycosyltransferase domain and its specific inhibitor moenomycin

Beta-lactams and glycopeptides antibiotics directed against enzymes involved in bacterial cell wall synthesis have generated bacterial resistance. Search for new antibiotic molecules is widely focused on bifunctional Penicillin-Binding Proteins (PBPs), with particular emphasis on their glycosyltransferase activity. This function catalyzes glycan chain polymerization of the cell wall peptidoglycan. This review summarizes recent results about biochemical characterization of bifunctional PBPs and enzymatic properties of the glycosyltransferase domain. Moenomycin, a well studied glycosyltransferase activity inhibitor has provided useful informations about lipid binding properties and about cellular role of bifunctional PBPs. These enzymes were shown to be a part of the multienzymatic complex involved in peptidoglycan biosynthesis. Furthermore, bifunctional PBPs are also present in the protein complex located at the site of septation during cell division. The glycosyltransferase domain of bifunctional PBPs remains unsufficently characterized: the structural analysis may lead to the development of novel antibacterials and to the understanding of the enzymatic properties, while genetic and cellular studies focused on bifunctional PBPs will provide a wealth of knowledge regarding cell growth and division.     

Antibacterial agents: patent highlights January to June 2002

A total of 48 patents dealing with disclosures on the different classes of antibacterial agents, including the beta-lactams, oxazolidinones, macrolides, quinolones, tetracyclines and miscellaneous antibacterial agents reported between January and June 2002 are selected for review. The miscellaneous agents section focused on the significant discovery of potential lead compounds as inhibitors of bacterial fatty acid synthase and peptide deformylase, and also included examples of novel peptidic antibiotics and pleuromutilin derivatives along with their antibacterial activities. Only a few patents disclosed novel agents in the quinolone and carbapenem areas. There are several patents disclosing improved formulation of old agents to increase their effectiveness and stability upon storage. Two patents disclosed effectiveness of antibiotic combinations with respect to the newer antibiotics linezolid and quinupristin/dalfopristin.     

Discovery of novel antibacterials

Importance of the field: Antibiotics have existed in the environment for millennia, but it has only been in the past 80 years that humans have used them systematically to treat infections. This battle between humans and bacteria has led to an alarming increase in resistance to all clinically useful antibacterial agents. Thus, there is an imperative need for new agents to combat these resistant strains of bacteria. Areas covered in this review: The topics covered include natural product screening, identification and validation of new antibacterial targets and approaches for the discovery and optimization of antibacterial compounds. Last, an assessment of the major challenges facing antibacterial discovery is presented. What the reader will gain: The current strategies and methodologies for discovering and designing new antibacterial agents are evaluated as to their potential for generating the next round of therapeutics. Each topic is presented in a general, basic manner and will hopefully be a useful resource for students and newcomers to the field. Take home message: New antibacterial agents are desperately needed to fight the increasing number of antibiotic resistant pathogenic bacteria. New methodologies as well as traditional approaches should both be used for discovering antibiotics to meet this serious medical need.     

Bacterial targets to antimicrobial leads and development candidates

The unabated spread of drug-resistant bacterial pathogens continues to pose a significant threat to patient health. However, there are now several new and improved derivatives from established classes of antibiotics that have recently been approved or are in late-stage development. In drug discovery, screening of new targets derived from genomic-based discovery stratagems has resulted in a number of potent antibacterial leads. Further optimization and development of these promising compounds offer the opportunity to develop new classes of antimicrobials that act through modes of action that are unlikely to be affected by resistance mechanisms defined to date. In addition, new discoveries in biochemical mechanisms of antibiotic action continue to help identify new approaches to design novel antibiotic analogs.     

Multitarget ligands in antibacterial research: progress and opportunities

Introduction: Resistance to current antibacterial therapies is an inevitability that represents a significant global health concern. Bacteria have the capacity to render all current drug treatments ineffective, which places a demand on the drug discovery community to constantly develop new antibacterial agents. Compounds that inhibit multiple biological targets, often referred to as multitarget ligands, are an inviting prospect in antibacterial research because, although they will not solve the issue of resistance, they might help to delay the onset.

Areas covered: This review covers some of the recent progress in identifying new ligands that deliberately interact with more than one essential biological target in bacteria. The two principal areas covered are inhibitors of DNA replication and cell wall biosynthesis.

Expert opinion: Antibacterial programs for the design of multitarget ligands present an important opportunity for production of antibacterial agents. Their longevity, due to slow development of resistance, is comparable to that seen with other successful agents – but is much improved over single-targeted agents for which resistance can appear in vitro overnight. The preclinical development of these agents will have to overcome the standard problems of antibacterial discovery. Such problems include optimization of characteristics favoring cell entry and particularly the demonstration of selectivity of inhibition of the desired multiple targets without inhibition of other bacterial or any mammalian functions.