Current Medicinal Chemistry - Anti-Infective Agents - Volume 1, Issue 3, 2002

The ß-lactam antibiotics perhaps form the best studied and most used (in volume and sales) antibiotics in the world today. The extensive and in many cases, uncontrolled use of the ß-lactam antibiotics, particularly in developing countries and for veterinary uses, has resulted in the evolution of resistance in many strains of bacteria. One common mechanism of resistance with ß-lactam antibiotics is the expression of a specific class of enzymes - the ß-lactamases - by the bacteria. These enzymes interact with and destroy the antibiotic, before it can exert its desired effect. Many (up to now 340) distinct ß-lactamases have been isolated and identified so far and various methods of classifying them reported. The particular ß-lactamases produced is dependent on factors that include the nature of the strain of bacteria and the particular antibiotic used. Since over the years, the usage of the ß-lactam antibiotics has changed depending on the discovery of new and superior members and on variations in usage in different countries, there has been a shifting pattern in the particular ß-lactamases produced over time. There is hence a continuing need to identify new ß-lactamases inhibitors which would be effective in combination with the newer antibiotics. This paper considers recent developments in identifying new classes and members of ß-lactamase inhibitors.

For nearly six decades, penicillins have been used widely to treat bacterial infections. The development of multidrug resistance, however, has reduced the effectiveness of β-lactams as antimicrobial drugs. A main contributor to b-lactam resistance is the production of β-lactamases, and the development of β-lactamase inhibitors has been one of the main strategies in antimicrobial drug development. In recent years, microbial resistance to existing β-lactamase inhibitors has emerged, spurring investigations in the area of β-lactamase dependent prodrugs that incorporate a bactericidal moiety. In a similar fashion cytotoxic prodrugs have been developed as a means of anticancer therapy.Recently, certain β-lactams have been identified as inhibitors of serine enzymes produced by viruses, fungi and mammals. Development of β-lactam inhibitors of enzymes which have active-site serine, such as human leukocyte elastase, human cytomegalovirus protein, prostate specific antigen, thrombin, herpesvirus, co-enzyme A independent transacylase, γ-aminobutyric acid (GABA) aminotransferase, and human cytosolic phospholipase A2, has attracted interest in all areas of medicinal chemistry. Efforts have been directed toward identification of the structure-activity relationship of the newly developed or modified β-lactams, as well as enrichment of the arsenal of existing methods for asymmetric synthesis and application of novel analytical techniques, such as ESIMS for β-lactam-enzyme complex identification. The present review intends to draw attention to the versatility of the β-lactams as serine enzyme inhibitors.

Peptide deformylase (PDF) has emerged as one of the most promising new targets for antimicrobial chemotherapy. PDF is an essential bacterial metalloenzyme that deformylates the N-formylmethionine of newly synthesised bacterial polypeptides. Although the enzyme has been known for over 30 years, it has proved difficult to isolate and characterise due to its apparent instability. However, recent progress in understanding the structure and function of PDF has greatly facilitated the drug discovery process. In this article we review the potential of PDF as an antibacterial target and highlight progress in the development of inhibitors of PDF. The field has evolved particularly rapidly through the use of high throughput screening and combinatorial techniques and the diverse series of structures exploited previously in other metalloenzyme programmes. Although many different structural classes of compounds have been reported as inhibitors of PDF, the real challenge has been in obtaining molecules with good antibacterial activity. Several PDF inhibitors have now been described that demonstrate potent in vitro antibacterial activity against a range of Gram-negative and Gram-positive drug resistant pathogens. Results in stringent animal models of infection suggest that for some of these molecules good in vitro activity translates into good in vivo efficacy. One of the most encouraging compounds reported, BB-83698, has shown activity against Streptococcus pneumoniae in both the neutropenic mouse thigh and lung infection models. These data suggest that PDF inhibitors are a promising new class of antibacterial agents with opportunities to treat respiratory and other bacterial infections.

N-Thiolated β-lactams are β-lactam compounds that have a sulfur substituent on the nitrogen center. They represent a broad and growing family of bioactive molecules. In this review we provide a summary of the known biological properties of the different classes of N-thiolated β-lactams, and the methods used to prepare them. Our discussion begins with the N-sulfonic acid derivatives, which include the well-known monobactam family of antibiotics, followed by the N-sulfonyl, N-sulfinyl, and N-sulfenyl β-lactams.

A review of recent developments in the field of anti-MRSA cephems is presented. The R.W. Johnson / Microcide collaboration seems to be the most advanced effort to date, but many other companies are continuing their efforts to develop a cephalosporin for use against serious Gram-positive infections such as MRSA. A detailed account of the progression of the MRSA cephem program at Bristol-Myers Squibb is provided. This work produced a number of compounds that had excellent biological activity, and were safe in a murine model of acute toxicity.

Multidrug-resistant Gram-positive bacteria have become an increasing problem for the management of serious infections. Also extended-spectrum β-lactamase producing Gram-negative bacilli is a growing concern. A number of novel parenteral or oral cephalosporins have been synthesized and evaluated in vitro in order to overcome these resistances. In particular, today research in the cephem field is more focused on narrow spectrum antibacterials. Unfortunately, many new compounds will not be studied in clinical setting because they only show a slight improvement over existing therapies that does not justify the excessive costs involved in the development of a new chemical entity. We believe that the continuous attempts to discover structural changes able to induce real improvements in the spectrum of action of cephalosporins are now unproductive, probably because there is no room for further really useful modifications.

Efforts to mimic the antibacterial properties of the polymyxin peptide antibiotics and the steroid antibiotic squalamine have resulted in the development of novel antimicrobial agents comprised of cationic steroids. These cationic steroid antibiotics (CSAs) display a range of antibacterial properties including effective bactericidal activity and the ability to permeabilize the outer membranes of gram-negative bacteria sensitizing them to hydrophobic antibiotics that ineffectively traverse the outer membrane. CSAs demonstrate membrane activity similar to that of many cationic peptide antibiotics and likely exert their bactericidal effects via the ‘carpet’ model. CSAs have been constructed in such a fashion that they are stable under acidic and basic conditions. Other examples have been assembled using functionality that is sensitive to pH, and these compounds tend to decompose under mildly basic conditions to yield endogenous or non-toxic components. These later compounds may prove useful in preventing microbial growth in food. The potential for systemic clinical use among membrane-active antibiotics may depend upon eukaryotic vs. prokaryotic cell selectivities. Examples of CSAs are bactericidal at low concentrations while displaying very weak or undetectable hemolytic activities. Other examples have proven to be very hemolytic. The cell selectivities of CSAs may depend upon recognition of the anionic charges of the membranes of prokaryotes.

Numerous defense peptides (cationic antimicrobial peptides) were isolated from eukaryotic systems and their functions were studied. In spite of size, primary sequences, and structures, most of them shared common features. They preferentially bind to lipid membranes of microbes and increase permeability of lipid membranes as a primary mode of action. The characteristics of cationic antimicrobial peptide different from conventional antibiotics make themselves a candidate for novel antimicrobial agents. In this review, we will provide a general overview of linear antimicrobial peptides with emphasis on aspects such as structure, biological mode, and structural parameters for activity and selectivity in vitro. And this review will focus on recent design and synthesis of novel peptide analogs with enhanced stability and selectivity.