New antibiotics that are active against resistant bacteria are required.
Bacteria have lived on the Earth for several billion years. During this
time, they encountered in nature a wide range of naturally occurring
antibiotics. To survive, bacteria developed antibiotic resistance
mechanisms. Therefore, it is not surprising that they have become
resistant to most of the natural antimicrobial agents that have been
developed over the past 50 years.16 This resistance increasingly limits
the effectiveness of current antimicrobial drugs. The problem is not
just antibiotic resistance but also multidrug resistance. In 2004, more
than 70% of pathogenic bacteria were estimated to be resistant to at
least one of the currently available antibiotics.17 The so-called ‘superbugs’
(organisms that are resistant to most of the clinically used
antibiotics) are emerging at a rapid rate. S. aureus, which is resistant
to methicillin, is responsible for many cases of infections each year.
The incidence of multidrug-resistant pathogenic bacteria is increasing.
The Infectious Disease Society of America (IDSA) reported in 2004
that in US hospitals alone, around 2 million people acquire bacterial
infections each year (http://www.idsociety.org/Content.aspx?idј4682).
S. aureus is responsible for half of the hospital-associated infections
and takes the lives of approximately 100 000 patients each year in the
USA alone.18 The bacteria produce a biofilm in which they are encased
and protected from the environment. Biofilms can grow on wounds,
scar tissues and medical implants or devices, such as joint prostheses,
spinal instrumentations, catheters, vascular prosthetic grafts and heart
valves.More than 70% of the bacterial species producing such biofilms
are likely to be resistant to at least one of the drugs commonly used in
anti-infectious therapy.14 In hospitals, there are also other examples of
Gram-positive (Enterococcus and Streptococcus) and Gram-negative
pathogens (Klebsiella, Escherichia, Enterobacter, Serratia, Citrobacter,
Salmonella and Pseudomonas); these hospital-inhabiting microbes are
Table 1 Anti-infective market in 200010
Compounds Market (US$ billions)
Cephalosporins 9.9
Penicillins 8.2
Other b-lactams 1.5
Antivirals excluding vaccines 10.2
Quinolones 6.4
Antifungals and antiparasitics 4.2
Aminoglycosides 1.8
Tetracyclines 1.4
Other antibacterials 6.1
Other anti-infectives 5.3
Total 55.0
Microbial drug discovery
AL Demain and S Sanchez
6
The Journal of Antibiotics
called ‘nosocomial bacteria.’More than 60% of sepsis cases in hospitals
are caused by Gram-negative bacteria.14 Among them, Pseudomonas
aeruginosa accounts for almost 80% of these opportunistic infections.
They represent a serious problem in patients hospitalized with cancer,
cystic fibrosis and burns, causing death in 50% of cases. Other
infections caused by Pseudomonas species include endocarditis, pneumonia
and infections of the urinary tract, central nervous system,
wounds, eyes, ears, skin and musculoskeletal system. This bacterium is
another example of a natural multidrug-resistant microorganism.
Although many strains are susceptible to gentamicin, tobramycin
and amikacin, resistant forms have also developed. These multidrug-
resistant bacteria make hospitals ‘‘dangerous places to be, especially
if you are sick, but even if not.’’19
Although we are seeing a steady increase in resistance in almost
every pathogen to most of the current antibiotics over time, not all the
antibacterial agents show the same rate of resistance development. For
example, antimicrobials such as rifampicin, which targets single
enzymes, are most susceptible to the development of resistance,
whereas agents that inactivate several targets irreversibly generate
resistance more slowly.
In addition to the antibiotic-resistance problem, new families of
anti-infective compounds are needed to enter the marketplace at
regular intervals to tackle the new diseases caused by evolving
pathogens. At least 30 new diseases emerged in the 1980s and 1990s
and they are growing in incidence. Emerging infectious organisms
often encounter hosts with no prior exposure to them and thus
represent a novel challenge to the host’s immune system. Several
viruses responsible for human epidemics have made a transition from
animal host to humans and are now transmitted from human to
human. HIV, responsible for the acquired immunodeficiency syndrome
(AIDS) epidemic, is one example. Although it has not been
proven, it is suspected that severe acute respiratory syndrome (SARS),
caused by the SARS coronavirus, also evolved from a different
species.20
In the early 1990s, after decades of decline, the incidence of
tuberculosis began to increase. The epidemic took place owing to
inadequate treatment regimens, a diminished public health system and
the onset of the HIV/AIDS epidemic. The WHO has predicted that
between 2000 and 2020, nearly 1 billion people will become infected
with Mycobacterium tuberculosis and that this disease will cost the lives
of 35 million people.
Sexually transmitted diseases have also increased during these
decades, especially in young people (aged 15–24 years). The human
papillomavirus, chlamydia, genital herpes, gonorrhea and HIV/AIDS
are examples. HIV/AIDS has infected more than 40 million people in
the world. Together with other diseases such as tuberculosis and
malaria, HIV/AIDS accounts for over 300 million illnesses and more
than 5 million deaths each year.
Additional evolving pathogens include the (i) Ebola virus, which
causes the viral hemorrhagic fever syndrome with a resultant mortality
rate of 88%; (ii) the bacterium Legionella pneumophila, a ubiquitous
aquatic organism that lives in warm environments, which causes
Legionnaire’s disease, a pulmonary infection; (iii) the Hantavirus,
which can infect humans with two serious illnesses: hemorrhagic fever
with renal syndrome and Hantavirus pulmonary syndrome; (iv) at
least three species of bacteria from the genus Borrelia, which cause
Lyme disease, an emerging infection. In this case, the infection is
acquired from the bite of ticks belonging to several species of the
genus Ixodes. Borrelia burgdorferi is the predominant cause of Lyme
disease in the US, whereas Borrelia afzelii and Borrelia garinii are
implicated in most European cases. The disease presentation varies
widely, and may include a rash and flu-like symptoms in its initial
stage, followed by musculoskeletal, arthritic, neurologic, psychiatric
and cardiac manifestations. In the majority of cases, symptoms can be
eliminated with antibiotics, especially if the treatment begins early in
the course of illness. However, late or inadequate treatment can lead to
‘late-stage’ Lyme disease that can be disabling and difficult to treat.21
(v) Other evolving pathogens include the Escherichia coli 0157:H7
(enterohemorrhagic E. coli), a strain that causes colitis and bloody
diarrhea by producing a toxin called Shiga toxin, which damages the
intestines. It is estimated that this bacterium causes infection in more
than 70 000 patients a year in the USA. Another example is (vi)
Cryptosporidium, an obligate intracellular parasite commonly found in
lakes and rivers. Cryptosporidium parvum is one of the common
species affecting the digestive and respiratory organs. Intestinal cryptosporidiosis
is characterized by severe watery diarrhea. Pulmonary
and tracheal cryptosporidiosis in humans is associated with coughing
and is frequently a low-grade fever. People with severely weakened
immune systems are likely to have more severe and more persistent
symptoms than healthy individuals.
In the developing world, nearly 90% of the infectious disease deaths
are caused by six diseases or disease processes: acute respiratory
infections, diarrhea, tuberculosis, HIV, measles and malaria. In both
the developing and developed nations, the leading cause of death by a
wide margin is acute respiratory disease. In the developing world,
acute respiratory infections are attributed primarily to seven bacteria:
Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenzae,
Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydophila
pneumoniae and Chlamydia trachomatis. In addition, the major viral
causes of respiratory infections include respiratory syncytial virus,
human parainfluenza viruses 1 and 3, influenza viruses A and B, as
well as some adenoviruses. These diseases are highly destructive in
economic and social as well as in human terms and cause approximately
17 million deaths per year, and innumerable serious illnesses
besides affecting the economic growth, development and prosperity of
human societies.22 Morse23 identified six general factors in the
emergence of infectious diseases: ecological changes, human demographics
and behavior, international travel, technology and industry,
microbial adaptation and change, and breakdown in public health
measures.24
One additional reason for developing new antibiotics is related to
their own toxicity. As with other therapeutic agents, the use of
antibiotics may also cause side effects in patients. These include
mild reactions such as upset stomach, vomiting and diarrhea (cephalosporins,
macrolides, penicillins and tetracyclines), rash and other
mild and severe allergic reactions (cephalosporins and penicillins),
sensitivity to sunlight (tetracyclines), nervousness, tremors and
seizures (quinolones). Some side effects are more severe and,
depending on the antibiotic, may disrupt the hearing function
(aminoglycosides), kidneys (aminoglycosides and polypeptides) or
liver (rifampin).
Bacteria have lived on the Earth for several billion years. During this
time, they encountered in nature a wide range of naturally occurring
antibiotics. To survive, bacteria developed antibiotic resistance
mechanisms. Therefore, it is not surprising that they have become
resistant to most of the natural antimicrobial agents that have been
developed over the past 50 years.16 This resistance increasingly limits
the effectiveness of current antimicrobial drugs. The problem is not
just antibiotic resistance but also multidrug resistance. In 2004, more
than 70% of pathogenic bacteria were estimated to be resistant to at
least one of the currently available antibiotics.17 The so-called ‘superbugs’
(organisms that are resistant to most of the clinically used
antibiotics) are emerging at a rapid rate. S. aureus, which is resistant
to methicillin, is responsible for many cases of infections each year.
The incidence of multidrug-resistant pathogenic bacteria is increasing.
The Infectious Disease Society of America (IDSA) reported in 2004
that in US hospitals alone, around 2 million people acquire bacterial
infections each year (http://www.idsociety.org/Content.aspx?idј4682).
S. aureus is responsible for half of the hospital-associated infections
and takes the lives of approximately 100 000 patients each year in the
USA alone.18 The bacteria produce a biofilm in which they are encased
and protected from the environment. Biofilms can grow on wounds,
scar tissues and medical implants or devices, such as joint prostheses,
spinal instrumentations, catheters, vascular prosthetic grafts and heart
valves.More than 70% of the bacterial species producing such biofilms
are likely to be resistant to at least one of the drugs commonly used in
anti-infectious therapy.14 In hospitals, there are also other examples of
Gram-positive (Enterococcus and Streptococcus) and Gram-negative
pathogens (Klebsiella, Escherichia, Enterobacter, Serratia, Citrobacter,
Salmonella and Pseudomonas); these hospital-inhabiting microbes are
Table 1 Anti-infective market in 200010
Compounds Market (US$ billions)
Cephalosporins 9.9
Penicillins 8.2
Other b-lactams 1.5
Antivirals excluding vaccines 10.2
Quinolones 6.4
Antifungals and antiparasitics 4.2
Aminoglycosides 1.8
Tetracyclines 1.4
Other antibacterials 6.1
Other anti-infectives 5.3
Total 55.0
Microbial drug discovery
AL Demain and S Sanchez
6
The Journal of Antibiotics
called ‘nosocomial bacteria.’More than 60% of sepsis cases in hospitals
are caused by Gram-negative bacteria.14 Among them, Pseudomonas
aeruginosa accounts for almost 80% of these opportunistic infections.
They represent a serious problem in patients hospitalized with cancer,
cystic fibrosis and burns, causing death in 50% of cases. Other
infections caused by Pseudomonas species include endocarditis, pneumonia
and infections of the urinary tract, central nervous system,
wounds, eyes, ears, skin and musculoskeletal system. This bacterium is
another example of a natural multidrug-resistant microorganism.
Although many strains are susceptible to gentamicin, tobramycin
and amikacin, resistant forms have also developed. These multidrug-
resistant bacteria make hospitals ‘‘dangerous places to be, especially
if you are sick, but even if not.’’19
Although we are seeing a steady increase in resistance in almost
every pathogen to most of the current antibiotics over time, not all the
antibacterial agents show the same rate of resistance development. For
example, antimicrobials such as rifampicin, which targets single
enzymes, are most susceptible to the development of resistance,
whereas agents that inactivate several targets irreversibly generate
resistance more slowly.
In addition to the antibiotic-resistance problem, new families of
anti-infective compounds are needed to enter the marketplace at
regular intervals to tackle the new diseases caused by evolving
pathogens. At least 30 new diseases emerged in the 1980s and 1990s
and they are growing in incidence. Emerging infectious organisms
often encounter hosts with no prior exposure to them and thus
represent a novel challenge to the host’s immune system. Several
viruses responsible for human epidemics have made a transition from
animal host to humans and are now transmitted from human to
human. HIV, responsible for the acquired immunodeficiency syndrome
(AIDS) epidemic, is one example. Although it has not been
proven, it is suspected that severe acute respiratory syndrome (SARS),
caused by the SARS coronavirus, also evolved from a different
species.20
In the early 1990s, after decades of decline, the incidence of
tuberculosis began to increase. The epidemic took place owing to
inadequate treatment regimens, a diminished public health system and
the onset of the HIV/AIDS epidemic. The WHO has predicted that
between 2000 and 2020, nearly 1 billion people will become infected
with Mycobacterium tuberculosis and that this disease will cost the lives
of 35 million people.
Sexually transmitted diseases have also increased during these
decades, especially in young people (aged 15–24 years). The human
papillomavirus, chlamydia, genital herpes, gonorrhea and HIV/AIDS
are examples. HIV/AIDS has infected more than 40 million people in
the world. Together with other diseases such as tuberculosis and
malaria, HIV/AIDS accounts for over 300 million illnesses and more
than 5 million deaths each year.
Additional evolving pathogens include the (i) Ebola virus, which
causes the viral hemorrhagic fever syndrome with a resultant mortality
rate of 88%; (ii) the bacterium Legionella pneumophila, a ubiquitous
aquatic organism that lives in warm environments, which causes
Legionnaire’s disease, a pulmonary infection; (iii) the Hantavirus,
which can infect humans with two serious illnesses: hemorrhagic fever
with renal syndrome and Hantavirus pulmonary syndrome; (iv) at
least three species of bacteria from the genus Borrelia, which cause
Lyme disease, an emerging infection. In this case, the infection is
acquired from the bite of ticks belonging to several species of the
genus Ixodes. Borrelia burgdorferi is the predominant cause of Lyme
disease in the US, whereas Borrelia afzelii and Borrelia garinii are
implicated in most European cases. The disease presentation varies
widely, and may include a rash and flu-like symptoms in its initial
stage, followed by musculoskeletal, arthritic, neurologic, psychiatric
and cardiac manifestations. In the majority of cases, symptoms can be
eliminated with antibiotics, especially if the treatment begins early in
the course of illness. However, late or inadequate treatment can lead to
‘late-stage’ Lyme disease that can be disabling and difficult to treat.21
(v) Other evolving pathogens include the Escherichia coli 0157:H7
(enterohemorrhagic E. coli), a strain that causes colitis and bloody
diarrhea by producing a toxin called Shiga toxin, which damages the
intestines. It is estimated that this bacterium causes infection in more
than 70 000 patients a year in the USA. Another example is (vi)
Cryptosporidium, an obligate intracellular parasite commonly found in
lakes and rivers. Cryptosporidium parvum is one of the common
species affecting the digestive and respiratory organs. Intestinal cryptosporidiosis
is characterized by severe watery diarrhea. Pulmonary
and tracheal cryptosporidiosis in humans is associated with coughing
and is frequently a low-grade fever. People with severely weakened
immune systems are likely to have more severe and more persistent
symptoms than healthy individuals.
In the developing world, nearly 90% of the infectious disease deaths
are caused by six diseases or disease processes: acute respiratory
infections, diarrhea, tuberculosis, HIV, measles and malaria. In both
the developing and developed nations, the leading cause of death by a
wide margin is acute respiratory disease. In the developing world,
acute respiratory infections are attributed primarily to seven bacteria:
Bordetella pertussis, Streptococcus pneumoniae, Haemophilus influenzae,
Staphylococcus aureus, Mycoplasma pneumoniae, Chlamydophila
pneumoniae and Chlamydia trachomatis. In addition, the major viral
causes of respiratory infections include respiratory syncytial virus,
human parainfluenza viruses 1 and 3, influenza viruses A and B, as
well as some adenoviruses. These diseases are highly destructive in
economic and social as well as in human terms and cause approximately
17 million deaths per year, and innumerable serious illnesses
besides affecting the economic growth, development and prosperity of
human societies.22 Morse23 identified six general factors in the
emergence of infectious diseases: ecological changes, human demographics
and behavior, international travel, technology and industry,
microbial adaptation and change, and breakdown in public health
measures.24
One additional reason for developing new antibiotics is related to
their own toxicity. As with other therapeutic agents, the use of
antibiotics may also cause side effects in patients. These include
mild reactions such as upset stomach, vomiting and diarrhea (cephalosporins,
macrolides, penicillins and tetracyclines), rash and other
mild and severe allergic reactions (cephalosporins and penicillins),
sensitivity to sunlight (tetracyclines), nervousness, tremors and
seizures (quinolones). Some side effects are more severe and,
depending on the antibiotic, may disrupt the hearing function
(aminoglycosides), kidneys (aminoglycosides and polypeptides) or
liver (rifampin).
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