Review Article http://dx.doi.org/10.3947/ic.2012.44.4.263 Infect Chemother 2012;44(4):263-268 pissn 2093-2340 eissn 2092-6448 Infection & Chemotherapy 항생제개발의역사및현황 송영구 연세대학교의과대학감염내과 The History of Antimicrobial Drug Development and the Current Situation Since development of the first antimicrobial agents in the 1940s, antimicrobial resistance has been an issue. Following the introduction of sulfonamides and penicillin, scientists discovered and developed a wide range of antimicrobials for treatment of bacterial diseases. Many new antimicrobials were discovered by systematic testing of soil microbes and many others were developed by chemical modification of existing agents. Discovery of new classes of antibacterial drugs slowed in the late 1960s. However, the speed with which bacteria develop resistance to antibiotics, in contrast with the slow development of new drugs, has led some experts to warn of a "post-antibiotic era." Judicious use of currently available antibiotics, through efforts such as public campaigns for 'appropriate antibiotic use', may help to conserve their effectiveness. However, even if we improve these practices, development of resistant bacteria will continue to occur, and new and better drugs will be needed. Clearly, a combination of traditional successful methods and modern technology will be needed for discovery and development of new classes of antibacterial drugs. In addition, policies that encourage and facilitate development of new antimicrobial agents are also needed. Young Goo Song Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Key Words : Antimicrobial agents, Drug development, Discovery, Antimicrobial drug resistance, History 서론 항생제가사용되기이전시대의황색포도알균에의한균혈증의사망률은 82% 에달했으며, 50세이상환자에서는 2% 만이생존할수있었다 [1, 2]. 이런면에서항생물질의발견및항생제의개발은현대의학을발전시키게된하나의커다란역사적사건임에틀림없다. 20세기후반반세기동안수많은새로운항생제가개발되었으며, 임상의사들은다양한감염질환의치료에어렵지않게여러항생제중적절한항생제를선택하여치료할수있었다. 그러나항생제가처음사용되기시작하던시기부터항생제내성에대한문제가제기되어왔으며, 이문제는최근에더욱심각해지고있다. 임상의사들은이전에항생제에잘듣던세균들이점차내성을갖게되는과정들을특별한대책없이지켜보고만있는실정이며, 이제는내성세균이점차확산되면서생명 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2012 by The Korean Society of Infectious Diseases Korean Society for Chemotherapy Submitted: August 7, 2012 Accepted: August 7, 2012 Correspondence to Young Goo Song Department of Internal Medicine, Yonsei University College of Medicine, Seoul 135-720, Korea Tel: +82-2-2019-3310, Fax: +82-2-3463-3882 E-mail: imfell@yuhs.acr www.icjournal.org
264 YG Song The History of Antimicrobial Drug Development and Current Situation www.icjournal.org 을위협하는중증감염증에대해선택할수있는항생제에도많은제한이따르게되었다 [3-7]. 항생제내성의출현과확산을감소시키기위해서는현재사용하고있는항생제를적절히사용하여내성출현을늦추는방법뿐만아니라, 새로운항생제의개발이반드시필요하다. 그러나새로운항생제개발에대한의사들의기대와는달리, 일부대형제약회사들은항생제개발분야에더이상투자하지않고점차손을떼고있는실정이다. 미국 FDA 에서새로승인되는항생제신약은지난 20여년간 56% 가감소된것으로나타나고있다 [8, 9]. 이와같은이유중의하나는새로운항생제개발의기술적어려움도있겠지만, 새롭게신약이개발되더라도적절한항생제사용에대한인식이낮은현재의료현실에서, 빠른내성획득으로인해개발비를보상할만한기간동안충분히사용되지못하고무용지물이될것이예상되기때문일것이다 [8, 10-13]. 결국새로운항생제의개발과적절한사용이동시에이루어지지않는한현재직면한항생제내성의문제는더욱더심각해질수있으며, 어떠한항생제에도듣지않는내성세균에의한감염으로인류는소위 Post-antibiotic eraʼ 에직면하게될수도있는상황이되었다 [3, 4, 6, 8, 14]. 본문에서는현대의학에서항생제가얼마나소중한물질이며얼마나신중하게사용되어야하는지에대한인식을일깨우기위한일환으로, 과거항생제개발의역사를짚어보고현재의상황과미래의항생제개발방향에대하여언급하고자한다. 자연물질과화학물질의시대 항균효과를보이는자연물질로는 1619 년페루에서최초로 cinchona 나무껍질의추출물을이용해말라리아에걸린스페인계통치자의아내를성공적으로치료한기록이있으며, 남미에서는아메바장염의치료에 ipecacuanha 뿌리가효과가있었다는기록이있다 [15]. 이시기에만들어진약제중 quinine, emetine 등은현재까지도사용되고있다. 1909 년에 Paul Ehrlich 는처음으로화학물질을이용한치료를시행하였는데, 606번째실험을통해 trypanosoma 에효과가있는물질을개발하는데성공하였다. Salvarsan 혹은 606호라고불리는이약제는매독의치료에도사용되었으며, 당시 마법의탄알 이라고불렸다 [15, 16]. 1932 년 Klarer 와 Mietzsch 에의해 azo 계열의염색약의일종인 Prontosil 혹은 sulfonamido chrysoidin 이합성되었으며, 1934 년독일의약리학자인 Gerhard Domagk 에의해사슬알균에효과가있다는것이증명되었다 [15]. 바로이때부터항생화학요법의황금시대가실제적으로시작되었다고할수있다. 1936 년영국의 Colebrook 와 Kenny 가산욕열의치료에 Prontosil 을사용하면서산욕열로인한사망률은급격히감소하게되었다. 당시 prontosil 이인체내에서는효과가있으나시험관내에서는항균효과가없다는사실에의문을가졌는데, 1937 년 Fuller 에의해 prontosil 이체내에서 p-amino-benzene sulfonamide (sulfanilamide) 로분리된후에야항균작용을나타낸다는사실이밝혀지면서이러한의문이풀리게되었다 [16, 17]. 스위스 의 Daniel Bovet 는 sulfanilamide 를직접만들어내는데성공하였으며, 사슬알균이나포도알균에대해매우효과적으로작용하여폐렴을비롯한많은세균성질환들이그이후점차정복되기시작하였다. 특히 70-90% 의사망률을보이던수막알균에의한수막염에사용하여사망률을 10% 정도로낮추는기적과도같은효과를볼수있었다 [18]. 화학자들은이약의효능을높이기위해화학적구조에변화를가하기시작하였으며, 그결과 1938 년에는폐렴알균폐렴에최초로효과가인정된 sulfapyridine 이만들어졌고, 이후부작용을줄인 sulfathiazole 과 sulfadiazine 등이개발되었다. 중증의치명적인감염질환에서의탁월한치료효과에근거하여, 의사들은위약 -대조군연구와같은체계적인임상시험을통한자료도없이, 저절로호전될수도있는가벼운감염질환들을포함한대부분의감염질환에서마법과도같은약제인항생제를무분별하게사용하게되었고, 저절로도회복될수있는감염질환들이마치항생제효과로회복된것으로믿게되었다. 이는항생제의효과를정확하게평가하기위한연구에서체계적인임상시험설계가얼마나중요한지를보여주는대목으로, 미래의항생제효과연구에서매우중요하게적용되어야할부분이다 [19]. 미생물로부터개발된항생제의시대 실제로는설파제이전인 1928 년 Alexander Fleming 이우연히세균을배양하는실험을하던중곰팡이가생긴배지에서는포도알균의배양이잘안되는것을발견하였고, 곰팡이에서무언가세균의성장을억제하는물질이나온다고생각하고이물질을추출해내는데성공하였으며 [20], 이물질을 penicillin 이라고명명하였다. 그러나정제기술이없어 penicillin 이발견된이후실제사용되기까지는 12년이라는오랜시간이걸렸다. 1941 년이되어서야처음인체에투여되었고, 몇년이지난후에야 penicillin 은완전히정제되어구조가밝혀졌으며, 대규모발효시설을갖춘미국에서대량생산이가능하게되어제2차세계대전중많은생명을구하게되었다. 그러나여기저기에서신비의명약처럼 penicillin 을무분별하게사용하는사례가증가하면서점차 penicillin 에내성을지닌세균들이생겨나게되었고, 8년정도흐른 1950 년쯤에는포도알균의 40% 가 penicillin 에내성을갖게되었으며, 1960 년쯤에는내성률이 80% 가되어 penicillin 의기적과도같았던효과는점차사라지게되었다 [3, 21]. Penicillin 에내성이생긴세균에대항해인류는 1959 년에메티실린을개발해냈지만 2년후바로메티실린에내성을갖는포도알구균이발견되었다. Fleming 은 1945 년 The New York Times 지에서, penicillin 의부적절한사용은황색포도알균에서내성을가진돌연변이종을유도하게되어내성균주에의한심각한감염증이발생할수있다고경고하였으나 [15], 항생제의오남용과내성균주출현의악순환은항생제가사용되기시작한초창기부터가장최근까지도개선되지않고있는문제가되었다. 이때부터생존을위한미생물의보이지않는투쟁과이를극복하려는인류의새로운항생제개발과의싸움은시작되었으며현재까지도지속되고있다.
www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.4.263 Infect Chemother 2012;44(4):263-268 265 Penicillin 의놀라운능력에감명을받아다른미생물의성장을억제하는유용한미생물을흙으로부터찾기위해일생을바친 Selman A. Waksman 과그의연구원들은 10,000 번이상의흙을배양하는실험을수없이반복하던중, 1943 년병든닭의목에서배양된특이한곰팡이가결핵균의성장을억제하는것을관찰할수있었고, 이물질을 streptomycin 이라고명명하였다. Waksman 은흙속의곰팡이나미생물로부터생성되어다른미생물의성장을억제하거나파괴시키는화학물질을총칭하여 antibiotics 라는용어를처음으로사용하였다 [15, 21]. 1944 년폐결핵으로죽어가고있는젊은여자환자에게 streptomycin 이처음으로투여되어그녀의생명을구했으며, 그로부터 10 년후미국에서결핵으로인한사망은극적으로줄어들기시작하였다. Fleming 과 Waksman 의발견이후사람들은항생제의놀라운능력을알게되었으며, 이후광범위 penicillin 들과 aminoglycosides 가발 견되었고, 다른대표적인항생제들이뒤이어개발되었다. 이에따라브루셀라증, 장티푸스, 아메바성자염등대표적인감염질환들이점차사라지기시작하였다 [15]. 1980 년대까지는주로자연물질이나다양한곳에서견본을얻은미생물로부터항균물질을추출해내는방법으로전혀새로운계열의항생제를개발하였으며, 1980 년대이후에는이전약제의화학구조를변화시켜약리작용을개선시키거나부작용을줄이는신약이많이개발되었다 [19]. 항생제개발현황 최근까지주요항생제들이개발되어시중에유통되기시작한시점을기준으로본항생제연대표는 Table 1과같다 [22]. 1983 년부터 2005 년까지 20여년간매 5년마다미국 FDA 에서승인된새로운항생 Table 1. Timeline a of Antimicrobial Therapy Year b Antibiotics Year Antibiotics Year Antibiotics Year Antibiotics 1910 Salvarsan 1962 Cloxacillin 1980 Piperacillin 1988 Teicoplanin 1912 Neosalvarsan 1962 Fusidic acid 1981 Amoxicillin/clavulanic acid 1989 Cefpodoxime 1935 Prontosil 1963 Fusafungine 1981 Cefperazone 1989 Enrofloxacin 1936 Sulfanilamide 1963 Lymecycline 1981 Cefotiam 1989 Lomefloxacin 1938 Sulfapyridine 1964 Gentamicin 1981 Latamoxef 1989 Moxifloxacin 1939 Sulfacetamide 1966 Doxacycline 1981 Netilmicin 1990 Arbekacin 1940 Sulfamethizole 1967 Carbenicillin 1982 Apalcillin 1990 Cefozidime 1942 Benzylpenicillin 1967 Rifampicin 1982 Ceftriaxone 1990 Clarithromycin 1942 Gramicidin S 1968 Clindamycin 1982 Micronomicin 1991 Cefdinir 1942 Sulfadimidine 1970 Cefalexin 1983 Cefmenoxime 1992 Cefetamet 1943 Sulfamerazine 1971 Cefazolin 1983 Ceftazidime 1992 Cefpirome 1944 Streptomycin 1971 Pivampicillin 1983 Ceftiroxime 1992 Cefprozil 1947 Sulfadiazine 1971 Tinidazole 1983 Norfloxacin 1992 Ceftibufen 1948 Chlortetracycline 1972 Amoxicillin 1984 Cefonicid 1992 Floroxacin 1949 Chloramphenicol 1972 Cefradine 1984 Cefotetan 1992 Loracarbef 1949 Neomycin 1972 Minocycline 1984 Temocillin 1992 Piperacillin/tazobactam 1950 Oxytetracycline 1972 Pristinamycin 1985 Cefpiramide 1992 Rufloxacin 1950 Penicillin G procaine 1973 Fosfomycin 1985 Imipenem/cilastatin 1993 Brodimoprim 1952 Erythromycin 1974 Talampicillin 1985 Ofloxacin 1993 Dirithromycin 1954 Benzathine penicillin 1975 Tobramycin 1986 Mupirocin 1993 Levofloxacin 1955 Spiramycin 1975 Bacampicillin 1986 Aztreonam 1993 Nadifloxacin 1955 Tetracycline 1975 Ticarcillin 1986 Cefoperazone/sulbactam 1993 Panipenem/betamipron 1955 Thiamphenicol 1976 Amikacin 1986 Ticarcillin/clavulanic acid 1993 Sparfloxacin 1955 Vancomycin 1977 Azlocillin 1987 Ampicillin/sulbactam 1994 Cefepime 1956 Phenoxymethylpenicillin 1977 Cefadroxil 1987 Cefixime 1999 Quinupristin/dalfopristin 1958 Colistin 1977 Cefamandole 1987 Roxithromycin 2000 Linezolid 1958 Demeclocycline 1977 Cefoxitin 1987 Sultamicillin 2001 Telithromycin 1959 Virginiamycin 1977 Cefuroxime 1987 Ciprofloxacin 2003 Daptomycin 1960 Methicillin 1977 Mezlocillin 1987 Rifaximin 2005 Tigecycline 1960 Metronidazole 1977 Pivmecillinam 1988 Azithromycin 2005 Doripenem 1961 Ampicillin 1979 Cefaclor 1988 Flomoxef 2009 Telavancin 1961 Spectinomycin 1980 Cefmetazole 1988 Isepamycin 1961 Sulfamethoxazole 1980 Cefotaxime 1988 Midecamycin 1961 Trimethoprim 1980 Cefsulodin 1988 Rifapentine a Data from [http://en.wikipedia.org/wiki/timeline_of_antibiotics] b The year shown indicates when a given drug was released onto the pharmaceutical market. This is not a timeline of the development of the antibiotics themselves.
266 YG Song The History of Antimicrobial Drug Development and Current Situation www.icjournal.org 제의수는 Fig. 1과같으며, 1980 년대이후새로개발되는항생제수는지속적으로감소추세임을알수있다 [3]. 1960 년대는매년 2.9 개의새로운항생제가 FDA 의승인을받았지만, 1990 년대는매년 2.2 개로감소하였으며, 2000 년이후에는매년 1.6 개정도로감소하였다 [8]. 계열이전혀다른새로운계열의항생제의수도 1930 년대에서 1960 년대까지는 13-14 개의새로운계열의항생물질이개발되었지만 ( 학자들에따라계열의분류에일부차이가있음 ), 1970 년대이후에는단지 5개의새로운항생제계열만이개발되었으며, 그나마이들중 2가지계열은국소항생제이다 (Fig. 2)[5]. 이와같은경향은향후선택할수있는항생제가점점감소하고있다는의미이며, 특히여러항생제에내성을보이는소위다제내성균에대한선택치료제가거의없다는것을의미한다. 미국감염학회에서는새로운항생제가가장필요한최고우선순위의병원균 6가지를정하여 (Acinetobacter baumannii, Aspergillus spp., ESBL-producing E. coli and Klebsiella spp., VRE, Pseudomonas aeruginosa, MRSA) 이들병원균에효과적인항생제개발의필요성을강조하고있는데, MRSA, VRE, 그리고 ESBL 생성균 에대해서는최근새롭게승인받거나심사중인항생제들이있으나, Acinetobacter 와 Pseudomonas 에대한새로운치료제는거의개발되지못하고있는실정이다. 최근미국 FDA 에서승인받았거나심사중인 6가지의새로운항생제들 (dalbavancin, faropenem, telavancin, ceftobiprole, oritavancin, iclaprim) 도새로운계열의항생제는없으며, faropenem 을제외하고는주요적응증은피부및연조직감염증이고, MRSA 를포함하는그람양성균에주로효과가있는약제들이다 [7]. 역사적으로도 1960 년대에서 1980 년대까지주로그람음성균 (Pseudomonas aeruginosa, Klebsiella pneumoniae, E. coli 등 ) 에초점을맞추어항생제가개발되던시기에그람양성균 (Staphylococci, Streptococcus pneumoniae, Enterococci 등 ) 에서의내성이증가하였으며, 1980 년대이후부터최근까지위에서언급한바와같이주로그람양성균 (MRSA, VRE 등 ) 에초점을맞추어항생제를개발하고있는현재에는다시그람음성균 (Pseudomonas aeruginosa, Acinetobacter baumannii, E. coli 등 ) 에서의내성이증가하는경향이다 [7, 8]. No. new antibacterial agents 18 16 14 12 10 8 6 4 2 0 1983-1987 1988-1992 1993-1997 1998-2002 2003-2005 Year Figure 1. New antibacterial agents approved by the FDA in the U.S from 1983 to 2005 (Data from Ref. 3). 향후항생제개발의방향 항생제가처음으로사용되기시작하던시기부터항생제내성의문제는지속되어왔다. 그러나 1970-1980 년대의항생제황금시대를지나온현재, 새로운항생제의개발속도는내성세균의출현속도를따라가지못하고있는실정이다. 내성세균에의한중증감염질환이 21세기의주요의료문제로대두되고있는이유이다. 새로운항생제가분명히필요한시기이기는하지만제약회사들은더이상항생제개발을위해투자할동인을가지고있지않다. 새로운항생제가개발되어시장에나오기까지평균 5-10 년이걸리며 4-8 억달러가넘는연구개발비용이소요되는반면 [10], 내성세균의출현으로시장에서의항생제수명은그리길지못하기때문에다른약제에비해항생제를개발할만한매력을느끼지못하고있는것이현실이다 [11, 19]. 또한심혈관계약물, 신경계약물, 정신과약물, 그리고항암제등의약물은장기간또는평생사용해야하는약제인반면, 항생제는길어야몇주정도의사용으로 Figure 2. Introduction of new classes of antibiotics for human use from 1930 to 2010 (Beta-lactams include three groups sometimes identified as separate classes: penicillins, cephalosporins, and carbapenems).
www.icjournal.org http://dx.doi.org/10.3947/ic.2012.44.4.263 Infect Chemother 2012;44(4):263-268 267 끝나기때문에제약회사들이매력을가질만큼이익을가져다주지못하는것이사실이다 [19]. 반면항바이러스제는그동안개발되어있는약제가많지않아그만큼경쟁을덜해도되며, 부적절한사용에대한문제가항생제에비해적으며, 급속도로치명적으로악화되는세균질환에비해만성질환이더많기때문에, 1980 년대이후지속적으로항바이러스제의개발은증가하고있다 [19]. 그러나이러한어려운상황에도불구하고새로운항생제개발은지속되어야한다. 단순히시장논리에만맡길것이아니라정부차원의과감한제도적, 정책적지원도필요하다. 제약회사들은화학구조를변형시켜새로운항생물질을찾는기존의방법에서벗어날필요도있다. 최근새로운계열의항생물질을찾기위해서는다시역사속의전통적인방법으로회귀하는방법이필요하다는제안이설득력을갖고있다. 새로운계열의항생제개발방향의열쇠는바로역사속에있다는말이다 [23]. 화학구조를변형시켜새로운항생물질을찾는방법은이제어느정도한계에다다랐다고생각된다. Penicillin 이나 streptomycin 을발견했던것처럼, 자연의흙에사는다양한미생물이나식물로부터항생물질을추출하던고전적인방법론에, 현대의다양하고발달된배양기술이나화학기술들을적용한다면, 과거에놓쳤을수도있었던새로운계열의항생물질을발견하는것은훨씬쉬운일이될것이다 [24]. 최근국내연구진이남해바다흙에사는미생물의일종인방선균에서 vancomycin 이나 linezolid 보다훨씬강력한새로운항생물질을추출해냈다는보도는제 2의항생제황금시대의서막을알리는신호탄이라고할수있으며, 또한향후새로운항생제개발방향을보여주는중요한연구결과라고할수있다. 또다른새로운방향은병인기전에관여하는세균의병독인자들을표적으로하는표적치료제의개발이다. 유전자수준에서접근하는미래지향적인방법으로항생물질개발의새로운분야가될수있을것이다 [25]. 어떠한항생제에도내성을보이는다제내성균에의한중증감염질환의문제에직면한현재, 과감한제도적, 정책적, 재정적지원을통한새로운항생제개발을유도하는공격적인전략과함께, 대한감염학회와대한화학요법학회에서공동으로추진하고있는 항생제올바로쓰기캠페인 등과같은방법을통한기존항생제의적절한사용을유도하는방어적전략이모두필요한때이다. 현재사용가능한항생제의수명을최대한길게유지하면서, 역사속의방법론과미래지향적인방법들을동원하여새로운항생제개발에박차를가한다면, 소위 postantibiotic eraʼ 를슬기롭게극복해나갈수있을것이다. References 1. Wenzel RP. The antibiotic pipeline - challenges, costs, and values. N Engl J Med 2004;351:523-6. 2. Skinner D, Keefer CS. Significance of bacteremia caused by Staphlyococcus aureus. Arch Intern Med 1941;68:851-75. 3. Alanis AJ. Resistance to antibiotics: are we in the postantibiotic era? Arch Med Res 2005;36:697-705. 4. Falagas ME, Bliziotis IA. Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era? Intern J Antimicrob Agents 2007;29:630-6. 5. Outterson K, Samora JB, Keller-Cuda K. Will longer antimicrobial patents improve global public health? Lancet Infect Dis 2007;7:559-66. 6. Talbot GH, Bradley J, Edwards JE Jr., Gilbert D, Scheld M, Bartlett JG. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis 2006;42:657-68. 7. Diekema DJ, BootsMiller BJ, Vaughn TE, Woolson RF, Yankey JW, Ernst EJ, Flach SD, Ward MM, Franciscus CLJ, Pfaller MA, Doebbeling BN. Antimicrobial resistance trends and outbreak frequency in United States hospitals. Clin Infect Dis 2004;38:78-85. 8. Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE Jr. Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 2004;38: 1279-86. 9. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, Scheld M, Spellberg B, Bartlett J. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1-12. 10. DiMassa JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ 2003;22:151-85. 11. Projan SJ. Why is big pharma getting out of antibacterial drug discovery? Curr Opin Microbiol 2003;6:427-30. 12. Powers JH. Development of drugs for antimicrobial-resistant pathogens. Curr Opin Infect Dis 2003;16:547-51. 13. Norrby SR, Nord CE, Finch R; European Society of Clinical Microbiology and Infectious Diseases. Lack of development of new antimicrobial drugs: a potential serious threat to public health. Lancet Infect Dis 2005;5:115-9. 14. Wenzel RP, Edmond MB. Managing antibiotic resistance. N Engl J Med 2000;343:1961-3. 15. Hoel D, Williams DN. Antibiotics: past, present, and future. Unearthing nature's magic bullets. Postgrad Med 1997;101: 114-8, 121-2. 16. Lloyd NC, Morgan HW, Nicholson BK, Ronimus RS. The composition of Ehrlich's Salvarsan: Resolution of a centuryold debate. Angew Chem Int Ed 2005;44:941-4. 17. Lesch JE: Prontosil. In: Lesch JE. The first miracle drugs: how the sulfa drugs transformed medicine. Oxford University Press; 2007;51 18. Schwentker FF, Gelman S, Long PH. The treatment of meningococcic meningitis. JAMA 1937;108:1407-8. 19. Powers JH. Antimicrobial drug development-the past, the present, and the future. Clin Microbiol Infect Dis 2004;10 (Supple 4):23-31. 20. Fleming A. The antibacterial action of cultures of a Peni-
268 YG Song The History of Antimicrobial Drug Development and Current Situation www.icjournal.org cillium, with special reference to their use in the isola tion of B. influenzae. Br J Exp Pathol 1929;10:226-36. 21. Levy SB. From tragedy the antibiotic era is born. In: Levy SB, The Antibiotic Paradox; How the misuse of antibiotics destroys their curative powers, 2nd ed. Cambridge, MA: Perseus Publishing; 2002:1-14. 22. http://en.wikipedia.org/wiki/timeline_of_antibiotics 23. Lewis K. Recover the lost art of drug discovery. Nature 2012; 485:439-40. 24. Fernandes P. Antibacterial discovery and development- the failure of success? Nature Biotechnol 2006;24:1497-503. 25. Clatworthy AE, Pierson E, Hung DT. Targeting virulence: a new paradigm for antimicrobial therapy. Nature Chemical Biology 2007;3:541-8.