Antibacterial drug discovery research, accompanied by clinical development, has historically been conducted by large pharmaceutical companies . Although the earliest antibiotics were ï¬rst identiï¬ed in academic laboratories such as those of Alexander Fleming (penicillin) and Selman Waksman (streptomycin) , pharmaceutical companies were responsible for successful strain optimisation, compound scale-up, formulation and clinical development activities that allowed anti-infective drug research to gain prominence as a viable area for corporate investment. After the successful commercialisation of penicillin following the Second World War, companies like Abbott, Beecham, Bristol, Glaxo, Lederle, Lilly, Merck, Pï¬zer, Roche, Schering and Squibb became leaders in antibiotic development and maintained active antibacterial research organisations for decades.
The increasing number of reports about emerging multi-drug resistant bacteria and the lack of genuinely new classes of antibacterial drugs suggest that we may face the beginning of a post-antibiotic era. The unmet need for new therapies to treat bacterial infections caused by drug-resistant microorganisms should be a strong incentive to boost antibacterial R&D. However, the pharmaceutical industry is gradually deserting the ï¬eld of antibiotic research and focusing its efforts on chronic diseases that require life-long daily treatment or on manifestations such as baldness or inadequate sexual performance, which have come to be considered as "diseases" deserving speciï¬c treatments . Every year, many new potential antibacterial drugs are presented at scientiï¬c conferences, but very few seem to be interesting enough for the pharmaceutical industry. The problem is accentuated by large pharmaceutical companies' insisting that they need ï¬nancial incentives before they can re-start their antibacterial drug development programmes. Solutions are urgently needed, and the time has come to re-think how antibacterial drugs are discovered, developed and made available for patient treatment.
Seventy years of antibiotic discovery, research and development by the
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Alexander Fleming, returning from his summer holidays in September 1928, discovered penicillin by looking at an agar plate where the growth of a mould, later identiï¬ed as Penicillium notatum,had inhibited growth of staphylococci. The story of Fleming's discovery is far better known than the story of how penicillin ï¬nally ended up being produced by many pharmaceutical companies at the end of World War II. Following his ï¬rst observation, Fleming cultivated the mould and obtained an active, but unstable, syrupy brown liquid from the mould juice. However, he never succeeded in completing the puriï¬cation process of penicillin and a dozen years passed before a group of Oxford scientists led by Howard Florey was able to make some progress. When, on 6 September 1939, Florey made his ï¬rst speciï¬c appeal for public funding to work on penicillin, he applied for £100, but received only £25. Eventually, repeated appeals for support were successful and enough money was made available for penicillin research. By the spring of 1940, the team was able to obtain a powder that was active in vitro and started testing it on mice. Production was carried out in the laboratory and subsequently the team struggled to produce penicillin in sufï¬cient quantities for use in patient treatment. By May 1941, the penicillin produced at Oxford University by a team of ï¬ve young laboratory technicians had enabled the drug to be tested on only six patients.
At the time, ï¬nancial gain was not a driving force of science. According to Florey: "The people have paid for this work and they should have the beneï¬ts made freely available to them." When Ernst Chain, a member of Florey's team, argued that the drug should be patented, at least to prevent unscrupulous use, Florey took advice from two top British scientists, who conï¬rmed that patenting of a public discovery would be considered unethical. On many occasions, Florey had presented his work to British pharmaceutical companies, but none was interested. There was also rationing in wartime Britain, and laboratory equipment and chemicals were difï¬cult to obtain. At about the same time, the Rockefeller Foundation agreed to help him in getting a US drug company commit itself to large-scale production. To promote the development of penicillin in America, the US government encouraged companies to collaborate in their work without fear of potential anti-trust violations. In 1942, Merck, Squibb, and then Pï¬zer, Abbott and Winthrop, were the ï¬rst companies to sign an agreement to share research and production information, and include other companies that contributed to solving the problem . Until the beginning of 1943, production of penicillin was still limited, but the treatment of soldiers began and by the end of the year the War Production Board (WPB) had recognised that much more penicillin had to be produced as quickly as possible. The ï¬rst ï¬ve companies were soon joined by 21 others, and all were given ï¬nancial assistance by theWPB. By D-day, 6 June 1944, penicillin production had reached 100 billion units per month - enough to treat 40,000 patients . Most other major classes of antibacterial drugs, such as cephalosporins, tetracyclines, macrolides, and quinolones, were discovered between the end of the 1940s and the early 1960s (Fig. 1). This was done mostly by screening cultures of various microorganisms for antibiotic activity. Following the discovery of a new class, R&D then focused on extending the antibacterial spectrum of existing compounds by means of semi-synthetic optimisation. One early example was the development of penicillinase-resistant penicillins in the early 1950s to treat infections caused by penicillin-resistant staphylococci that had emerged following the therapeutic use of penicillin.
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During the 1960s and 1970s, the antibacterial drug industry emerged globally. By the early 1970s, more than 270 antibiotics had been produced . More new products were introduced and proï¬ts followed. For example, by 1980, the market for third- and fourth-generation cephalosporins was increasing at the rate of nearly 30% a year . In the 1980s, there were already so many antibiotics on the market that the projected proï¬ts from the development of new antibacterial drugs were seriously reduced. Pharmaceutical companies started to invest in R&D of new drugs for chronic illnesses, where long-term daily treatment is often necessary; this is considered one of the major reasons for the scarcity of new antibiotics in the 1990s .
Fewer new antibacterial drugs available for patient treatment
Although, for economic reasons, pharmaceutical companies have become increasingly interested in developing drugs for the treatment of chronic diseases, the data presented above might suggest that the antibiotic pipeline is not running dry. However, many of these new compounds do not represent true innovation, but are additions to existing classes of drug. Even the ketolides and the glycylcyclines, which are presented by pharmaceutical companies as new classes, originate from known classes. Although at present they overcome existing resistance, the risk is that resistance to these new agents will emerge faster than for a drug with a truly new mechanism of action. There are already fears that resistance to the recently approved ketolide telithromycin will quickly emerge in pneumococci . The two novel glycopeptides - dalbavancin and oritavancin - have a chemical structure close to that of vancomycin. Though less toxic than vancomycin and with fewer drug interaction problems, they will certainly encounter resistance. Another problem with oritavancin is that, because of its slow elimination, it can still be found in a patient's body 100 days after administration; this is a feature likely to foster emergence of resistance and complicate the drug's approval process by the Food & Drug Administration (FDA). In recent years, the pharmaceutical industry has generally not been very good at producing new drugs. Globally, since 1991, R&D spending has doubled, but has increased only slightly faster than revenues . The number of new molecular entities approved each year by the FDA fell from 53 in 1996 to 21 in 2003. For antibacterial drugs, research has focused on the DNA sequences of microorganisms and on potential new targets. High-throughput screening of large numbers of compounds for action on DNA and biochemical targets was found more complicated, time-consuming and expensive than expected, and it did not provide the compounds that it promised [13,48]. Almost since the beginning of drug R&D, it has been easier to develop copycat compounds with no obvious clinical advantage over existing ones, but different enough to get a patent and be marketed. Because their advantage is not obvious to the prescriber or the patient, these "me-too" drugs, as Merrill Goozner dubbed them, require increased marketing efforts: "Important new drugs do not need much promotion. Me-too drugs do!". This is the case with antibacterial drugs, too. Many large pharmaceutical companies have one ï¬‚uoroquinolone in their portfolio and compete with each other for the same indications and market. In the case of carbapenems, the drugs imipenemcilastatin and meropenem have for a long time been the only ones in this class. Since most hospitals decided to have one or the other on their formulary, thus limiting market competition, consumption has been maintained at a fairly low level and resistance is not a major problem except in particular high user hospitals. This situation will certainly change with the expected arrival of several other carbapenems on the market.
A recent review of antibiotic patents conï¬rms that, as for other drugs, pharmaceutical companies are still working more at modifying or combining existing antibacterial compounds than trying to ï¬nd new chemical structures that could lead to new classes of antibacterial agents. Indeed, the oxazolidinones represent the ï¬rst new antibiotic class in 25 years its ï¬rst member, linezolid, having been licensed in 2000. As for publicly funded research, recent terrorist attacks have somewhat shifted funding priorities from a focus on emerging infectious diseases, including ï¬ghting antimicrobial-drug resistance, to the prevention of bioterrorism - the best example being Project Bioshield, a comprehensive effort on the part of the US to develop and make available modern, effective drugs and vaccines to protect citizens against potential attack by biological and chemical weapons or dangerous pathogens.
Who will develop and market new antibacterial drugs?
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If new antibacterial agents are discovered, the remaining problem will be whether they will be developed and marketed. Because antibacterial drugs are given for short courses, they represent a small market as compared to drugs for chronic diseases that often require daily, life-long treatment. In an environment of increasing regulations and where the approval of any drug depends on demonstration of its efï¬cacy and the way in which it will be manufactured, the risks of marketing an antibiotic are considered higher than for other drugs. First, developing an antibiotic is potentially more difï¬cult because the mode of action might differ from one bacterial species to another, and the new agent must be tested against all species. Second, the new antibiotic must be as effective as existing ones against susceptible strains, but must also be effective against bacterial strains that have acquired resistance to existing drugs. Third, increasing concern about overuse and misuse among physicians and the general public has led to a general decrease in antibiotic use in several European countries and in the United States. Fourth, there is increasing pressure from health care and insurance systems to use fewer and cheaper antibiotics, and despite renewed alerts about emerging resistance, most infections are still treatable with existing antibacterial drugs. Fifth, new agents speciï¬cally launched to target resistance, i.e. linezolid and quinupristin-dalfopristin, have not captured the market that they were projected to capture [47,56]. Finally, resistance to a new agent will eventually develop in connection with the commercialisation and use of any new antibacterial drug, as shown by the recent reports of linezolid resistance in methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium . The time lapse between the patenting and the commercialisation of a new drug is on average 10 years, which leaves a comparatively short period of market exclusivity before the drug may be copied by generic producers. But pharmaceutical companies want a rapid and high return on investment and have therefore turned to the development of a few potential "blockbuster" drugs, since selling large quantities of one product makes a higher proï¬t. Very few antibacterial drugs reach the status of "blockbuster". In 2000, amoxicillin-clavulanate, with sales of USD 1.3 billion, was the only antibiotic in the list of the top 20 prescription drugs  and ranked 16th despite intensive marketing . Its sales were about one-third those of anti-ulcerant Prilosec R and cholesterol-lowering LipitorR , listed as number 1 and 2, respectively.
Net Present Value" and its inï¬‚uence on antibacterial-drug R&D
A key parameter for the way that the pharmaceutical industry decides on priorities is the Net Present Value (NPV) of projects. This is a means of determining the value of a given project after projecting for expenses and revenues in the future and discounting for the potential investment value of investment in the project . The NPV is usually risk-adjusted, most risk being associated with the earlier stages of the project. Antibacterial drugs are not especially attractive when NPV is considered. For example, Projan estimated that the risk-adjusted NPV of an injectable antibiotic targeting gram-positive bacteria was less than one-tenth of that of a particular musculoskeletal drug. Oral antibiotics, which can be marketed in the community - where approximately 90% of consumption occurs - are more attractive to the industry. According to a 2001 estimate from the Tufts University Center for the Study of Drug Development, the average cost of bringing a pharmaceutical compound through screening, chemistry, pre-clinical development and clinical testing is USD 800 million . Although this ï¬gure has been cited by many, it has also been challenged. The Public Citizen/Congress Watch, for example, came up with the value of USD 71 million, using another method of calculation, adjusting for tax deductibility of R&D expenses. The truth probably lies somewhere in between.
Antibiotic combinations , Antibiotic synergism Combination of antibiotics have enhanced activity when tested together compared with each antibiotic alone (e.g. 2 + 2 = 6)
e.g. ampicillin+gentamicin in entercoccal carditis (1) Additive effect
Combination of antibiotics has an additive effect (e.g. 2 + 2 = 4)
e.g. combination of two -lactam antibioticsb ñ Antibiotic antagonism Combination in which the activity of one antibiotic interferes with the activity of the other (e.g.2 + 2 < 4).
Basic mechanisms of antibiotic action
(1) Disruption of -lactam antibiotics ïPenicillins, cephalosporins andbbacterial cell wall ñ cephamycins, carbapenems and monobactams, -lactam combinationsb-lactamase inhibitor/b
ñ Polypeptides ,ïBacitracin, polymyxins , ñ Drugs used for treatment of mycobacterial infections
ïIsoniazid, ethinamide, ethambutol, cycloserine
Basic mechanisms of antibiotic action
Inhibition of protein synthesis
ñ Acting at 30S ribosomes
ñ Acting at 50S ribosomes
Basic mechanisms of antibiotic action
Inhibition of nucleic acid synthesis
ñ Acting on DNA replication
ñ Acting on RNA synthesis
Mechanisms of antibiotic resistance
1. Production of -lactamasesAG modifying enzymesbenzymes destroying and modifying AB
2. Decrease of cell membrane permeability
3. Active efflux of AB from cell
4. Modification of AB target sites
Genetics and spread of drug resistance
Viridans Streptococci â†’S.pneumoniae
E.faecium â†’ S.aureus
Mechanisms of resistance
ïProduction of enzymes inactivating
âˆ’ Main mechanism of -lactam antibioticsbresistance in
Ù Penicillin-resistant S.aureus
Ù Ampicillin-resistant E.coli
âˆ’ Production of enzymes modifying antibiotics
âˆ™ Aminoglycosides, chloramphenicol
Resistance mechanisms: inactivating enzymes
(1)Degrading enzymes will bind to
the antibiotic and essentially degrade it
or make the antibiotic inactive
(2)Blocking enzymes attach side chains to
the antibiotic that inhibit its function.
Mechanisms of resistance : (1)Antibiotics are removed via active efflux pump
(2) Universal efflux pump
(3) specific efflux pump
(4) quinolones, tetracyclines, chloramphenicol
Alterations in penicillin binding proteins
Major reason for resistance against Î²-lactam antibiotics
MRSA; MRSE ñ methicillin resistant S.aureus
PRSP ñ penicillin resistant S.pneumoniae Horizontal gene (mecA) transfer is likely