The Economic Conundrum for Antibacterial Drugs.

While resistance to antibacterial drugs is increasing globally, it is unevenly distributed. The number of cases that are truly difficult to treat remain below the number required to drive an adequate market for needed new therapies. Without a sufficient market, companies pursuing these drugs risk financial failure. Here, I explore, at least briefly, the current situation and the financial risks to companies. I provide potential solutions to the failed market.

Eight more ways to deal with antibiotic resistance.

The fight against antibiotic resistance must be strengthened. We propose actions that U.S. government agencies and private sector entities can take to build a more comprehensive effort. These actions can increase the viability of investing in new antibiotics, ensure the quality and stewardship of all antibiotics, and make responses to emerging resistance more informed. Success requires the thoughtful exercise of federal authority and a firm commitment to share data and reward developers for the value generated with new, life-saving antibiotics.

Innovation, Nontraditional Antibacterial Drugs, and Clinical Utility.

In this Viewpoint, I argue that our view of antibacterial discovery, development, and commercial potential requires a balance between innovation and clinical utility. I suggest that important new clinical utility may be more important to value than whether the compound in question belongs to a novel chemical class or attacks a novel antibacterial target. Novelty in this regard may increase the risk of scientific or clinical failure. So-called nontraditional approaches to antibacterial therapy are often innovative. The attendant challenges depend on whether the compound can be a stand-alone therapy, part of a fixed-dose combination, or whether it is adjunctive to standard therapy. Suitability for pharmacokinetic-pharmacodynamic studies and antimicrobial susceptibility testing is also an important consideration.

Antibacterial Drugs: The Last Frontier.

Our pipeline of antibacterial drugs is woefully lacking in our most high priority areas of medical need. In the absence of a reasonable return on their investment in antibacterial drugs, large companies have, for the most part, abandoned the area. Private investment in the research and development of these agents is plummeting, and public support, while important, cannot entirely replace this loss. Small companies have replaced the large ones in providing pipeline compounds. They are more susceptible to financial strain leading to the very real risk of bankruptcy as recently demonstrated by Achaogen and Melinta. I recommend taking three steps to ameliorate this impending crisis. We should provide financial support for the market preferably through a market entry reward or transferable exclusivity vouchers. To achieve this goal, we need to aggressively recruit professionals and patients to our cause who have been or will be affected by a lack of effective antibacterials. Our expert infectious disease societies must provide more timely clinical guidelines for therapy of resistant infections such that recently approved drugs will be used when indicated. We need regulation or legislation requiring manufacturers of antibacterial susceptibility testing devices to provide the ability to test new drugs in a timely manner.

Personal View of the Antibiotic Value Proposition.

In this brief viewpoint, I present four examples from my life in the practice of medicine and infectious diseases that illustrate both the miracle of antibiotics and the despair when they fail. There is the patient with pneumococcal pneumonia that was rapidly cured but also a disastrous outbreak of highly resistant Pseudomonas infection in a ward of severely burned patients where antibiotic treatment was ultimately futile. I note the utility of a new antibiotic in treating otherwise highly resistant Serratia infections. Finally, I discuss a patient with extensively resistant tuberculosis who came under my care.

5,5,6-Fused tricycles bearing imidazole and pyrazole 6-methylidene penems as broad-spectrum inhibitors of beta-lactamases.

Beta-lactamases are serine- and metal-dependent hydrolases, produced by the bacteria as defense against beta-lactam antibiotics. Commercially available inhibitors such as clavulanic acid, sulbactam, and tazobactam, which are currently used in the hospital settings, have reduced activity against newly emerging beta-lactamases. Bacterial production of diverse beta-lactamases including class-A, class-C, and ESBLs has motivated several research groups to search for inhibitors with a broader spectrum of activity. Previously, several novel 6-methylidene penems bearing, [5,5] [5,6] and [5,5,5] heterocycles have been synthesized in our laboratory and were shown to be potent and broad-spectrum beta-lactamase inhibitors. As a continuation of our previous work and in order to extend the structure-activity relationships, in this paper, we describe herein the synthesis and in vitro, in vivo activities of several novel 5,5,6-fused tricyclic heterocycles attached to the 6-methylidene penem core. The compounds presented in the current paper are potent and broad-spectrum inhibitors of the TEM-1 and AmpC beta-lactamases. In combination with piperacillin, their in vitro activities showed enhanced susceptibility to class A- and C-resistant strains studied in various bacteria. Some of the newly synthesized compounds such as 12a-c were shown to have in vivo activity in the acute lethal infection model against TEM-1 producing organisms. The 5,5,6-fused heterocyclic ring cores such as 21, 25, and 35 reported here are hitherto unknown in the literature.

Structure-activity relationship of 6-methylidene penems bearing 6,5 bicyclic heterocycles as broad-spectrum beta-lactamase inhibitors: evidence for 1,4-thiazepine intermediates with C7 R stereochemistry by computational methods.

The design and synthesis of a series of 6-methylidene penems containing [6,5]-fused bicycles (thiophene, imidazole, or pyrazle-fused system) as novel class A, B, and C beta-lactamase inhibitors is described. These penems proved to be potent inhibitors of the TEM-1 (class A) and AmpC (class C) beta-lactamases and less so against the class B metallo-beta-lactamase CcrA. Their in vitro and in vivo activities in combination with piperacillin are discussed. On the basis of the crystallographic structures of a serine-bound reaction intermediate of 2 with SHV-1 (class A) and GC1 (class C) enzymes, compounds 14a-l were designed and synthesized. Penems are proposed to form a seven-membered 1,4 thiazepine ring in both class A and C beta-lactamases. The interaction energy calculation for the enzyme-bound intermediates favor the formation of the C7 R enantiomer over the S enantiomer of the 1,4-thiazepine in both beta-lactamases, which is consistent with those obtained from the crystal structure of 2 with SHV-1 and GC1.

An update on tetracyclines.

The tetracyclines are a family of related natural products that were originally discovered by virtue of their antibacterial activities. As one of the earliest antibiotics to be marketed after penicillin and streptomycin, and because of their convenient oral dosing, tetracyclines have achieved wide clinical usage. However, this widespread clinical use, in addition to their use in animal feed, and even as an antibiotic spray for fruit and other crops, has produced widespread resistance that ultimately has limited the clinical utility of the entire family of tetracycline antibiotics. More recently, however, there has been renewed interest in this antibiotic class, with attempts being made to identify compounds capable of evading common bacterial resistance mechanisms and to search for potential uses beyond antibacterial therapy. This review will discuss the identification of 9-glycylamido-tetracyclines (glycylcyclines) and related compounds that have successfully evaded most bacterial resistance mechanisms, resulting in the approval of the first glycylcycline, tigecycline, for clinical use.

Inactivation of mprF affects vancomycin susceptibility in Staphylococcus aureus.

A chemically generated mutant of Staphylococcus aureus RN4220, GC6668, was isolated that had a fourfold increase in resistance to vancomycin. This phenotype reverted back to susceptibility by insertional mutagenesis with Tn917. In a selected set of revertants, Tn917 insertion was mapped to a unique chromosomal region upstream of mprF, a recently described gene that determines staphylococcal resistance to several host defense peptides. The genetic linkage between the vancomycin susceptibility and Tn917 insertion was then confirmed by transduction backcrosses into both GC6668 and GISA isolates, MER-S12 and HT2002 0127. Northern blot analysis, insertional inactivation and complementation experiments showed that mprF mediates vancomycin susceptibility in S. aureus. The inactivation of mprF by Tn917 insertion in HT2002 0127 caused a significant increase in the binding of vancomycin to the cell membranes. This observation serves as a likely mechanism of the increased vancomycin susceptibility associated with mprF inactivation.

The abandonment of antibacterials: why and wherefore?

The pharmaceutical industry is currently abandoning its antibacterial discovery research efforts. This seems to be part of a cyclical pattern in this therapeutic area. The reasons behind these ongoing cycles of feast and famine are multiple, but most revolve around the perception of market opportunities from the continuing emergence of resistance, balanced against the difficulties in the discovery of novel antibacterial compounds, the costs of development and the general regulatory and financial environment in which companies find themselves. Relief for the industry will require both regulatory and legislative action at a time when this will be politically difficult to achieve. In the meantime, the problems of antimicrobial resistance are not going away.

Research and Development of Antibiotics: The Next Battleground.

Antibiotic research has been hindered by a perfect storm consisting of scientific challenges, regulatory uncertainties, difficult markets, and industrial consolidation. At the same time, antibiotic resistance is making the medical need for a robust antibiotic pipeline ever more urgent. The Food and Drug Administration in the United States, following their European colleagues, has made important progress in correcting its position as part of this perfect storm and in providing less expensive and streamlined pathways for antibiotic development. But the economics of antibiotic development and marketing remains a potential stumbling block to reinvigorating antibiotic research within the pharmaceutical industry. The current situation is reviewed in this viewpoint article.

Hydrophobic acetal and ketal derivatives of mannopeptimycin-alpha and desmethylhexahydromannopeptimycin-alpha: semisynthetic glycopeptides with potent activity against Gram-positive bacteria.

The effect of introducing hydrophobic groups onto the disaccharide portion of the mannopeptimycins has been examined. Under acid-catalyzed conditions dimethyl acetals and ketals react on the terminal mannose of the disaccharide moiety of mannopeptimycin-alpha and the cyclohexylalanyl analogue 2. The preferentially formed monofunctionalized 4,6-acetals and -ketals display potent antibacterial activities against Gram-positive microorganisms, including MRSA, PRSP, and VRE pathogens.

New ß-lactam-ß-lactamase inhibitor combinations in clinical development.

Tazobactam was the most recent ß-lactamase inhibitor to be approved in 1993. Since the approval of piperacillin-tazobactam, the complexity of ß-lactamase-mediated resistance among Gram-negative bacilli has increased enormously. After more than 20 years since the first such combination, amoxicillin-clavulanic acid, was approved, several new ß-lactam-ß-lactamase inhibitor combinations have reached late-stage (phase II and beyond) clinical trials. These include ceftolozane-tazobactam (2:1, ratios of ß-lactam to ß-lactamase inhibitor in parentheses), ceftazidime-avibactam (4:1), ceftaroline-avibactam (1:1), and imipenem-cilastatin-MK-7655 (2:2:1 and 4:4:1). Avibactam and MK-7655 are diazabicyclooctane (DABCO) inhibitors and thus not ß-lactams themselves; they include class A carbapenemases and class C enzymes within their spectra of activity. Ceftolozane is an antipseudomonal cephalosporin, and tazobactam is used to protect it against extended spectrum ß-lactamases to which it is labile. Additional novel combinations are in preclinical development. This review will focus on the biochemistry, antimicrobial activity, pharmacodynamics, and clinical development of these novel combinations.

Overcoming the challenges to developing new antibiotics.

In order to meet the challenges of our current medical need to address infections caused by highly resistant pathogens, we propose the use of superiority trial designs. The proposed trials may or may not be statistically powered. All require extensive preclinical justification. The designs could use either historical or active controls. For historically controlled trials we propose two approaches for defining the control response rate to therapy; (1) the use of pharmacometrics from modern trials and (2) the use of a concurrent observational study. Designs for active controlled trials could be (1) standard of care+test vs. standard of care alone or (2) standard of care vs. test article. The second approach requires extensive justification to show that the test article will be of sufficient efficacy to allow ethical use as a single agent.