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HISTORICAL NOTE
Michigan State University, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan 49008
ABSTRACT
Infections have represented for a long time the leading cause of death in humans. During the 19th century, pneu-
monia, tuberculosis, diarrhea and diphtheria were considered the main causes of death in children and adults.
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Only in the late 19th century did it become possible to correlate the existence of microscopic pathogens with the
development of various diseases. Within a few years the introduction of antiseptic procedures had begun to re-
duce mortality due to postsurgical infections. Sanitation and hygiene played a significant role in the reduction
of the mortality due to several infectious diseases. The introduction of the first compounds with antimicrobial
activity succeeded in conquering many diseases.
In this review we analyzed, from a historical perspective, the development of antibiotics and the circumstances
that led to their discovery. The first compound with antimicrobial activity was introduced in 1911 by Erlich.
He focused his research activity on the discovery of a “magic bullet” to treat syphilis. Afterwards, Foley and
colleagues brought penicillin to the forefront. Streptomycin represents the first drug discovered for the treatment
For personal use only.
of tuberculosis, and its development included the first use of clinical trials. Finally, with the development of
cephalosporins, the introduction of new antimicrobial compounds with broad activity against Gram-positive
and also some Gram-negative bacteria began.
67
68 Zaffiri et al.
TABLE 1 Historical brief overview from the development of sulfa antimicrobials to antibiotic therapy up to cephalosporins
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For personal use only.
“606” due to the fact that it was the 606th compound Forneau (1872–1949) and Tréfouël (1897–1977) in 1935
tested by Ehrlich. This organoarsenic compound was demonstrated that Prontosil was a prodrug that was
later called Salvarsan. It represented the most used an- metabolized to sulfanilamide. This was then commer-
timicrobial drug until the 1940s [5]. However, despite cialized as Prontolyin [9]. Sulfonamide antibiotics have
its wide use and success, the mechanism of action re- been used for almost a century. They reached particular
mained unclear. Arsphenamine was known to convert popularity in the United States when, despite the early
to an active form in the body where it was toxic for doubts of the medical community, Prontosil was used
spirochetes and other parasites. to cure Franklin Delano Roosevelt, Jr. (1914–1988), the
Prontosil (1932) represents not the first discovered U.S President’s son, who was affected by a septic strep
antimicrobial but, more importantly, the first to be throat infection [10].
widely known [6]. Continuing Ehrlich’s work on the
effect of dye on microorganisms, two chemists, Klarer
(1898–1953) and Mietzsch (1896–1958), synthesized HISTORICAL USE AND MECHANISM
sulfonamidochrysoidine as part of a research study to OF ACTION OF SULFONAMIDES
prove the efficacy of dye as an antibacterial [7]. How-
ever, only through Domagk’s efforts (1895–1964) in Sulfonamides are bacteriostatic antimetabolite drugs
1932, was the first sulfa antibiotic introduced. He was which induce the inhibition of folate synthesis. They
able to prove the property of this component of the sul- are analogues of para-aminobenzoic acid (PABA)
fonamides in a murine model of Streptococcus pyogenes and act as competitive inhibitors of the enzyme
systemic infection [8]. Subsequent studies directed by dihydropteroate synthetase (DHPS). Blocking the
FIGURE 1 a) Paul Ehrlich (1854–1915); b) Alexander Fleming (1881–1955); c) Howard Florey (1898–1968); d) Selman Waksman
(1888–1973); e) Albert Schatz (1922–2005); f) Giuseppe Brotzu (1895–1955); g) Edward Abraham (1913–1999); h) Guy Newton
(1919–1969).
synthesis of folates, they induce the inhibition of DNA, to sulfonamides is very common and mediated by
RNA and protein synthesis [11]. Sulfonamides have different mechanisms: decreased permeability, active
broad- spectrum activity against both Gram-positive efflux pump, genetically mutated forms of DHPS, and
and Gram-negative bacteria. They were used mostly increased production of PABA [11,18,24–25].
to cure uncomplicated urinary tract infections and
Nocardia-related infections [12,13]. Sulfacetamide is
used for topical and ophthalmic bacterial infections FLEMING, FLOREY AND THE
[14,15]. Sulfadoxine is largely used in combination with SERENDIPITOUS DISCOVERY OF
pyrimethamine to treat or prevent malaria, especially PENICILLIN
when caused by Plasmodium falciparum [16,17]. The
most widely used sulfonamide is sulfamethoxazole, The concept of the antimicrobial treatment was revolu-
which is usually combined with pirymethoxazole due tionized by the work of Alexander Fleming (1881–1955)
to their synergistic activity in inhibiting subsequent (Figure 1b) and his famous discovery. He joined the In-
steps in folate synthesis [11]. They are bacteriostatic oculation Department at St. Mary Hospital in London
antibiotics active against susceptible forms of strep- at the beginning of the 20th century. His interest in mi-
tococci, Staphylococcus aureus, including cutaneous crobiology and antiseptics brought him to the discov-
infection from community acquired methicillin re- ery of one the most important drugs of the last century,
sistant Staph. aureus (MRSA) [18,19]. Moreover, the penicillin [26].
sulfonamides are active against oral anaerobes and While studying the antimicrobial properties of
some Gram- negative rods such as Escherichia coli and lysozyme, which he discovered earlier by adding his
Haemophilus influenza [20,21]. In addition, the combi- own nasal mucous to a culture plate [27], Fleming no-
nation is used for the treatment and the prophylaxis ticed an unusual phenomenon on an old culture plate
of two of the most common opportunistic infections in of Staphylococcus aureus [28]. The growth of these com-
immunocompromised patients: Pneumocystis jiroveci mon bacteria was inhibited by the presence of a con-
pneumonia and toxoplasmosis [22,23]. Resistance taminating blue mold. Interestingly, he reported in his
C 2012 Informa Healthcare USA, Inc.
70 Zaffiri et al.
paper (1928) that those plates were exposed and, there- was completely extracted from cultures of Penicillium
fore, contaminated with several micro-organisms, in- notatum isolated by Fleming himself. The need to pro-
cluding Penicillium notatum. However, the rest of the duce larger quantities of penicillin, especially for the
experiments conducted by Fleming and his colleagues treatment of soldiers involved in the war, led Florey to
truly opened the way for the antibiotic era. He de- collaborate with researchers in the U.S. (1941–1942). In
scribed in detail the characteristics and the growth re- 1943, Mary Hunt, also known as Moldy Mary, work-
quirement of the mold, and he tested other molds to ing in the Northern Regional Research Laboratory at
evaluate their antimicrobial activity. He developed a Peoria, Illinois, isolated Penicillium chrysogenum from
technique to detect the amount of penicillin produced a moldy cantaloupe found in a grocery market [34].
in a culture broth, called the ditch-plate method. Fi- By the end of the same year, mass production of peni-
nally, he described the amount of inhibition and the cillin began in several countries including the U.S., UK
effect of doubling the dilutions of his “inhibitor” yel- and Australia, where the new antibiotic was first made
low fluid, similar to our concept of minimum inhibitory available for civilian use.
concentration (MIC) and disk diffusion, and still ex-
tremely valuable today in the clinical setting [28–29].
Unfortunately, Fleming was not able to demonstrate HISTORICAL USE AND MECHANISM OF
the therapeutic value of penicillin due to the instability ACTION OF PENICILLINS
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FIGURE 2 Chemical structure of (a) arsphenamine, (b) penicillin, (c) streptomycin, and
(d) cephalosporin c.
extended-spectrum or aminopenicillins, and broad- around the 6-aminopenicillanic acid presented a new
spectrum or antipseudomonal penicillins. class of penicillinase-resistant penicillins: oxacillin, me-
The emergence of resistance has been one of the ma- thicillin, cloxacillin and dicloxacillin [35,59–61]. These
jor drives in the development of new types of peni- antibiotics are also known as anti-staphylococcal peni-
cillins. The cleavage of the beta-lactam ring is the major cillins, because they present a narrow spectrum of ac-
mechanism of resistance to beta-lactam antibiotics [39]. tivity compared to penicillin G. They are only used
The penicillinases are a specific group of enzymes of for the treatment of methicillin-sensitive Staphylococ-
the beta-lactamase family, which have the ability to hy- cus aureus (MSSA). It is important to highlight the very
drolyze the beta-lactam ring. They were initially identi- narrow spectrum of activity and the rapid emergence
fied in 1940 in E. coli strains but rapidly spread to other of MRSA (methicillin resistant Staphylococcus aureus)
bacteria [40]. In order to fight the spreading of the re- strains. The first report of the emergence of a MRSA
sistance mediated by beta-lactamase, inhibitors of these strain was in England in 1961[62] and in less than 20
enzymes were developed, starting in 1970 with the in- years MRSA was endemic in the U.S. [63].
troduction of clavulanic acid and followed by sulbac- The major expansion of the penicillins came through
tam and tazobactam, which are now broadly used in the work of Dr. Rolison at the Beecham Research Lab-
combination with broad- and extended-spectrum peni- oratories between 1940 and 1960. The goals were to
cillins [41]. identify the chemical structure with antibacterial activ-
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The narrow-spectrum penicillin group includes ity, to expand the spectrum of activity, and to improve
penicillin V (1944), penicillin G (1945), procaine peni- the bioavailability and oral absorption. Isolation of the
cillin (1947), and benzathine penicillin (1954). Penicillin 6-aminopenicillanic acid (1959) made possible the
G is active against Gram-positive cocci and rods and development of semisynthetic penicillins and the in-
Gram-negative cocci, and variably active against anaer- troduction of methicillin (1960) [60] and ampicillin
obes. Unfortunately, the widespread use of penicillin (1961) [64].
G after its introduction induced a generation of re- Ampicillin and amoxicillin were the first antibi-
sistant strains of bacteria. By 1957, more than 80% of otics of the second generation of penicillins or broad-
hospitals already reported the presence of a penicillin- spectrum penicillins. Ampicillin was introduced to
For personal use only.
resistant strain of Staph. aureus [42,43]. In addition, the achieve better coverage against Gram-negative bacte-
percentage of penicillin-resistant strains of Streptococ- ria, but it was soon recognized that strains of these
cus pneumoniae also kept increasing in the U.S. [44]. Fi- organisms possess variable susceptibility. They pre-
nally, strains of Neisseria gonorrhea have demonstrated sented identical chemical structure but amoxicillin
resistance to penicillin G when it was widely used for demonstrated higher serum concentration when ad-
the treatment of meningitis [45]. Despite the synergistic ministered orally [65]. Second-generation penicillins
effect on enterococci when administered together with are active against many bacteria including non-
an aminoglycoside, resistant strains of enterococci with penicillinase-producing strains of streptococci and
intrinsic resistance to penicillin G are increasing [46]. staphylococci, enterococci, L. monocytogenes, Clostridia
However, penicillin G is still considered the recom- spp. and Bacillus anthracis. Among the Gram-negative
mended treatment for S. pyogenes, Streptococcus agalac- bacteria these penicillins are active against H. influen-
tiae, group C and G streptococci, and Listeria monocyto- zae, E. coli, Salmonella, and Shigella [34].
genes infections [47–50]. Amoxicillin (1972) is considered the drug of choice
Probably the two most dramatic effects of the in- in the treatment of acute otitis media and upper airway
troduction of the penicillin were the treatment of infections caused by Strep. pyogenes [66,67]. Amoxi-
rheumatic fever and syphilis [51–54]. While acute cillin also demonstrates activity against Enterococcus
rheumatic fever and the consequent rheumatic heart faecalis in the treatment of uncomplicated urinary
disease remain a major cause of morbidity and mor- tract infections but, considering the high incidence
tality throughout the world, with an estimated 12 mil- of resistance of E. coli and Enterobacteriaceae strains,
lion people affected globally, in the U.S. a recent study amoxicillin is not widely used for these pathogens
showed an incidence of 14.8 cases per 100,000 hospi- [68]. Extremely important is the role of amoxicillin
talized children [55]. The continuous decline in the in- in the treatment and eradication of Helicobacter pylori,
cidence of acute rheumatic fever is mostly due to the given the carcinogenic risk associated with this in-
widespread use of antibiotic for the treatment of acute fection [69–71]. Finally, amoxicillin is widely used for
pharyngitis [56]. The benzathine penicillin G, which is the treatment of urethritis and cervicitis in pregnant
still the recommended treatment for early and latent women [72,73]. Ampicillin remains the drug of choice
syphilis, induced a decline in morbidity and mortal- for the treatment of pneumococcal pneumonia in
ity of syphilis by almost 90% between 1945 and 1975 infants and children when the strains are sensitive, as
[57,58]. well as the drug of choice for listeriosis [50,74].
The rapid emergence of penicillin-resistant staphy- The next generation of penicillins is represented by
lococci prompted research for pharmacological alter- carbenicillin (1957), tircacillin (1971) and piperacillin
natives. At the end of the 1950s, the semi-synthesis (1977). These extended-spectrum antibiotics are active
C 2012 Informa Healthcare USA, Inc.
72 Zaffiri et al.
against Gram-positive cocci, anaerobes and Gram- Between 1940 and 1952, Waksman isolated and re-
negative bacteria. Moreover, these drugs resist the ported on more than 10 different chemical substances
chromosomal beta-lactamases of certain organisms, with antimicrobial activity [84]. Of these, the most fa-
such as Enterobacter species and Pseudomonas aerugi- mous and influential was streptomycin [85]. In Septem-
nosa. The combination piperacillin- tazobactam (1989) ber 1943, the assiduous work of one of Waksman’s
was introduced in 1995 and is probably the most collaborators, Albert Schatz (1922–2005) (Figure 1e),
widely used, given its high activity against Gram- brought about the isolation of streptomycin from a
positive bacteria, including streptococci and entero- culture of Streptomyces griseus [86]. In less than a
cocci, but it is not active against methicillin-resistant month, a sample of streptomycin was sent to Mayo
staphylococci. However, the major advantage of this Clinic in order to allow William Feldman (1892–1974)
combination is activity against Gram-negative bacilli to conduct toxicology studies in animal models [87].
and in particular P. aeruginosa [75]. Subsequently, the collaboration between Feldman and
Hinshaw (1902–2000) led to the first clinical trials on
tuberculosis patients, less than a year after discovery
[88,89]. However, the effect of streptomycin on severe
THE FIGHT AGAINST TUBERCULOSIS cases of diffuse tuberculosis was undermined
AND THE DISCOVERY OF STREPTOMYCIN was undermined by the serious side effects and the
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its clinical manifestations, represented the most com- ward, the para-amino salt of salicylic acid (1944) was
mon cause of death in young adults. Other than un- synthesized by Lehman (1898–1989) [94,95], rapidly
successful attempts with tuberculin, isolated by Koch followed by the isonicotinic acid hydrazide (INH) in
(1843–1910) in 1892 [79,80], and light radiation, intro- 1952 [96]. This “triple therapy” resulted in predictable
duced by Finsen (1860–1904) at the beginning of the cures for 90% to 95% of patients with tuberculosis
19th century [81], there was no real hope for the treat- [93,97].
ment of Mycobacterium tuberculosis infections. Isolation
in a sanatorium provided the rest and improvement in
the sanitary conditions necessary for the initial recov-
ery, while confining the source of the infection from the HISTORICAL USE AND MECHANISM
general population [82]. OF ACTION OF STREPTOMYCIN
Following the discovery of penicillin and its suc-
cess in the treatment of bacterial infections, the drug Streptomycin (Figure 2c) is a protein synthesis inhibitor
company Merck strongly sustained the research of a and a bactericidal antibiotic. It binds to the small 16S
soil scientist at Rutgers University in New Jersey [77]. r RNA of the 30S subunit of bacterial ribosome, lead-
Selman Waksman (1888–1973) (Figure 1d) was born in ing to codon misreading and inhibition of protein
Ukraine and emigrated to the U.S. in 1910, where he synthesis [98]. The principal use remains against my-
started working in the field of soil microbiology. His cobacterial infections, and as a fourth agent along with
systematic and repetitive methods of working allowed isoniazid, rifampin and pyrazinamide in treating tu-
him to expand the knowledge about soil bacteriology berculosis [99,100]. Mutations of the ribosomal proteins
and the microbiological influence of different species are the basis of streptomycin resistance in mycobacte-
on each other. He established that as many as 50% of ria [101]. Moreover, the risk of ototoxicity and nephro-
the actinomyces found in soil were able to exert an in- toxicity limit the contemporary use of streptomycin in
hibitory effect on the growth of microorganisms. Waks- favor of ethambutol [99].
man essentially introduced the concept of antimicro- Streptomycin has been shown to be active in
bial activity, describing the effect of small molecules vitro and in vivo against Gram-negative microorgan-
made by a microbe which antagonized the growth of isms such as Brucella spp., Klebsiella granulomatis and
other microbes [83]. Already in 1932, The American Na- Klebsiella pneumoniae, E. coli, Proteus spp., Aerobac-
tional Association against Tuberculosis was supporting ter aerogenes, Francisella tularensis, Haemophilus ducreyi,
Waksman’s search for an antibiotic substance against Haemophilus influenzae and Yersinia pestis, as well as
the mycobacterium tuberculosis produced by soil mi- Gram-positive bacteria such as Streptococcus viridans
crobes. and Enterococcus faecalis [102–107].
FROM THE SEWER SYSTEM TO cal activity could be increased markedly by N-acylation
INDUSTRIAL PRODUCTION: of the side chain [114,115]
CEPHALOSPORINS Further industrial development of semisynthetic
cephalosporins depended upon their ability to mod-
Chronologically, the cephalosporins are the second ify the α-aminoadipoyl side chain in cephalosporin C
class among beta-lactam antibiotics to be discovered to other chemical moieties that confer advantageous
and developed, following the penicillins. The chemical antimicrobial activity [116,117]. The first cephalosporin
structure of cephalosporins contains a beta-lactam ring released for clinical use developed in this manner
fused to a six-membered ring containing a sulfur and a was cephalothin (cefalothin), introduced in 1964 by Eli
nitrogen atom. Among the most frequently prescribed Lilly and Company, and it was available only for par-
and clinically relied upon antibiotics in the U.S., these enteral use. Another among the early semisynthetic
pharmaceutical agents account for a significant share modifications of the C-7 side chain of the cephem nu-
of hospital expenditures [108]. cleus was the addition of a d-phenylglycyl moiety
In July 1945, Giuseppe Brotzu (1895–1955) (Figure that produced cephalexin, the first oral cephalosporin
1f) isolated a fungus identified as Cephalosporium acre- [118]. Since then, a large number of semisynthetic
monium from sewer water in Cagliari in Sardinia, Italy. derivatives with increased potency and antibacterial
The starting point of his research was the observa- spectrum have been introduced, with selection for clin-
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tion that the incidence of typhoid fever in the city of ical use based on antibacterial spectrum, pharmacoki-
Cagliari was curiously less than in the rest of Italy or netics, side effects and cost [119].
Europe. Using culture filtrates from the sewer system,
Brotzu found that this fungus inhibited the growth of HISTORICAL USE AND MECHANISM
certain Gram-negative organisms: Salmonella typhi, S. OF ACTION OF CEPHALPSPORINS
paratyphi B, Y. pestis, Brucella melitensis, Vibrio cholerae
and Staph. aureus. By contrast, strains of E. coli and As ß-lactam antibiotics, cephalosporins are primarily
Shigella dysenteriae that he tested exhibited resistance bactericidal, and a key mode of action involves inter-
[109]. Since then, other natural cephalosporins have ference with bacterial cell wall synthesis. Antibacte-
For personal use only.
been found to be produced by species of soil bacte- rial activity of individual cephalosporins is variable
ria. Unable to proceed with further development in and affected by several factors, including the abil-
Italy by himself, in 1946 Brotzu provided cultures of his ity to resist degradation by enzymes and the ability
fungus to Oxford University. In September 1948, Ed- to penetrate the bacterial cell wall. Classification of
ward Abraham (1913–1999) (Figure 1g), a Fleming stu- cephalosporins by generation is a convention whereby
dent, commenced investigations into the products of individual agents are grouped and described accord-
Brotzu’s microorganism. Abraham subsequently col- ing to in vitro antimicrobial activity [119]. In general,
laborated with Guy Newton (1919–1969) (Figure 1h), cephalosporins have not historically been antibiotics
at Sir William Dunn School of Pathology. of choice for therapy against penicillin-resistant Strep-
Among the first compounds isolated in July 1949 tococcus pneumonia, MRSA or Staphylococcus epidermis,
was cephalosporin P, so named because it was ac- E. faecalis, Mycoplasma pneumoniae, Clostridium difficile,
tive only against Gram-positive bacteria [110]. Shortly or Chlamydia pneumoniae [119]. Progressive generations
thereafter, a second compound was found in culture of cephalosporins exhibit incremental improvements
filtrates from which cephalosporin P had been re- with respect to Gram-negative antimicrobial properties
moved. This second compound was initially named over the preceding generation, often with decreased ac-
cephalosporin N, as it was active against Gram- tivity against Gram-positive organisms.
negative bacteria, as well as Gram-positive ones. The first-generation cephalosporins, such as the par-
Cephalosporin N was subsequently determined to be enteral drugs cephalothin (1962) and cefazolin (1970),
a penicillin, having a D-α-aminoadipoyl side chain, as well as the oral agent cephalexin (1967), are the most
and it was renamed penicillin N [111]. While investi- active of all cephalosporins against Gram-positive bac-
gating penicillin N, a third compound was separated teria, methicillin-susceptible staphylococci, and non-
upon fractionation that was also determined to have enterococcal streptococci [118, 120–123]. One of the
antibacterial activity and was called cephalosporin C second-generation semisynthetic derivatives, cefaclor
(Figure 2d). Abraham and Newton published their ob- (1977), became available in the United States in 1979.
servations and the structure of cephalosporin C in 1961 As a group, the second-generation cephalosporins are
[112]. less effective against Gram-positive microbes while
While cephalosporin C was believed to have poten- being more effective in clinical use with Gram-
tial by itself as a therapeutic agent, because it was not negative microbes, including H. influenzae, E. aerogenes
degraded by staphylococcal penicillinase, its intrinsic and certain Neisseria, than those agents classified as
activity was so low that clinical use would mandate first-generation. Of note, the only second-generation
very large doses. Upon continuing their investigations, cephalosporin that crosses the blood brain barrier is ce-
Abraham and Newton found that its antistaphylococ- furoxime, which is used to treat meningitis [124–128].
C 2012 Informa Healthcare USA, Inc.
74 Zaffiri et al.
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