Antibacterial Agents PDF

 DEFINITIONS ANTIMICROBIALS → is a wider term that includes all agents that act against microorganisms, namely bacteria, fungi, viruses and protozoa. ANTIBACTERIALS → act only on bacteria. Broadly defined, this term encompasses chemicals, compounds, agents th...

 DEFINITIONS ANTIMICROBIALS → is a wider term that includes all agents that act against microorganisms, namely bacteria, fungi, viruses and protozoa. ANTIBACTERIALS → act only on bacteria. Broadly defined, this term encompasses chemicals, compounds, agents that act against bacteria, including antibiotics. ANTIBIOTICS → are produced naturally by microorganisms and kill or inhibit the growth of other microorganisms (today even wholly or partly produced by synthesis). ALL ANTIBIOTICS ARE ANTIBACTERIALS BUT NOT ALL ANTIBACTERIALS ARE ANTIBIOTICS Antibacterials and antibiotics disrupt essential processes or structures in the bacterial cell. Depending on their effects, the agent is said to be bactericidal or bacteriostatic: o a bactericidal drug kills the bacteria o a bacteriostatic drug stops bacterial growth Bactericidal = antibiotics that kill bacteria Bacteriostatic = antibiotics that inhibit the growth of ARE BACTERICIDAL DRUGS bacteria (i.e. prevent the bacteria from continuing to MORE CLINICALLY EFFECTIVE grow/proliferate) without killing bacteria THAN BACTERIOSTATIC AGENTS? Antibiotics can be bacteriostatic for some pathogens and bactericidal for others.  DEFINITIONS Antibacterials and antibiotics can either have a broad or narrow spectrum of activity: o broad-spectrum drugs inhibit a wide range of bacteria. o narrow-spectrum drugs are more specific and only active against certain groups or strains of bacteria.  ANTIBIOTIC TARGETS IN BACTERIA There are four main antibiotic targets in bacteria: o the cell wall and membranes that surround the bacterial cell o the machineries that make the nucleic acids (DNA and RNA) o the machinery that produce proteins (the ribosome and associated proteins) o the synthesis of folic acids SELECTIVE ACTION ON METABOLIC PATHWAYS OF BACTERIA → NO TOXICITY  β-lactams are a wide range of antibiotics, the first of which to be discovered was penicillin, which Alexander Fleming identified in 1928. All β-lactam antibiotics contain a β-lactam ring. Bacteria can develop resistance to β-lactams via several routes, including the production of enzymes that break down the β-lactam ring. Penicillins are the most commonly prescribed antibiotics, with amoxicillin being the most common in the class. Broad-spectrum  “I did not invent penicillin. Nature did that. I only discovered it by accident.” Alexander Fleming, 1928 Fleming – together with Howard Florey and Ernst Chain, who devised methods for the large-scale isolation and production of penicillin – earned the 1945 Nobel Prize in Physiology/Medicine.  Prontosil, a sulfonamide, was the first commercially available antibiotic, developed in 1932. In the present day, sulfonamides are rarely used, partially due to the development of bacterial resistance, but also due to concern about unwanted effects such as damage to the liver of patients. FOLIC ACID BIOSYNTHESIS Sulphonamides compete with para-aminobenzoic acid for the enzyme dihydropteroate synthase; this inhibits the synthesis of dihydropteroic acid, a precursor of dihydrofolic acid and tetrahydrofolic acid. Trimethoprim inhibits the enzyme dihydrofolate reductase, an enzyme critical to the synthesis of tetrahydrofolic acid. Sulfamethoxazole- trimethoprim combination is active against Gram-negative and Gram- positive organisms including E. coli, Streptococci and Staphylococci. The antibacterial spectrum does not include Pseudomonas or Mycobacterium spp.  Tetracyclines are broad-spectrum antibiotics, active against both Gram-positive and Gram-negative bacteria. Their use is decreasing to increasing instances of bacterial resistance. In the past, tetracyclines have been extensively involved in food biotechnology and used in animals for prophylaxis and growth promotion → impact on environment and public health Tetracyclines interfere with the attachment of the tRNA to mRNA-ribosome complex  Chloramphenicol is a broad-spectrum antibiotic, it acts by inhibiting protein synthesis, and thus growth and reproduction of bacteria. No longer used as a first line drug because of the increased resistance. Quinolones are widely used for urinary tract infections, as well as other hospital-acquired infections where resistance to older classes of antibiotics is suspected. Resistance to quinolones can be particularly rapid in its development Discovered in 1987, lipopeptides are the most recent class of antibiotics. Daptomycin is the most commonly used member of the class; it has a unique mechanism of action, disrupting several aspects of cell membrane function in Gram positive bacteria. This unique mechanism of action also seems to be advantageous in that, currently, incidences of resistance to the drug seem to be rare – though they have been reported ANTIBIOTIC APPROVED OR YEAR YEAR RELEASED RESISTANT MICROBE IDENTIFIED RELEASED IDENTIFIED Penicillin 1941 Penicillin-resistant Staphylococcus aureus 1942 Penicillin-resistant Streptococcus pneumoniae 1967 Penicillinase-producing Neisseria gonorrhoeae 1976 Vancomycin 1958 Plasmid-mediated vancomycin-resistant 1988 Enterococcus faecium Vancomycin-resistant Staphylococcus aureus 2002 Amphotericin B 1959 Amphotericin B-resistant Candida auris 2016 Methicillin 1960 Methicillin-resistant Staphylococcus aureus 1960 Extended-spectrum 1980 (Cefotaxime) Extended-spectrum beta-lactamase- producing 1983 cephalosporins Escherichia coli Azithromycin 1980 Azithromycin-resistant Neisseria gonorrhoeae 2011 Imipenem 1985 Klebsiella pneumoniae carbapenemase (KPC)- 1996 producing Klebsiella pneumoniae Ciprofloxacin 1987 Ciprofloxacin-resistant Neisseria gonorrhoeae 2007 Fluconazole 1990 (FDA approved) Fluconazole-resistant Candida 1988 Caspofungin 2001 Caspofungin-resistant Candida 2004 Daptomycin 2003 Daptomycin-resistant methicillin-resistant 2004 Staphylococcus aureus Ceftazidime-avibactam 2015 Ceftazidime-avibactam-resistant KPC-producing 2015 Klebsiella pneumoniae Antibiotic resistance is considered nowadays as one of the greatest threats to human health. Cases of antibiotic resistance are constantly reported, and the time needed for bacteria to become resistant to newly introduced antibiotics, is getting shorter. Number of deaths and the main causes in 2019 and the projection of number of deaths due to AMR infections in 2050. Gray areas represent other causes of deaths.  Resistance to antibacterial drugs Antibiotic resistance is the ability of bacteria to “protect” themselves against the effects of an antibiotic → resistant bacteria will survive and increase in numbers. From a clinical perspective, resistance means that a bacterium can grow in the antibiotic concentrations reached in the body during standard therapy → using that antibiotic for this infection will most likely result in treatment failure. Bacteria have two alternative pathways to acquire resistance: o random changes in the bacterial DNA, mutations, may provide resistance by chance o acquisition of resistance genes from other bacteria nearby → horizontal gene transfer If a resistance mechanism gives an advantage to the bacterium it may be maintained, and it will be passed on to coming generations as the bacterium divides, or be passed along by horizontal transfer.  Resistance to antibacterial drugs MUTATIONS HORIZONTAL GENE TRANSFER  Resistance to antibacterial drugs Intrinsic resistance is the innate ability of a bacterial species to resist activity of a particular antibiotic. This can also be called “insensitivity” since it occurs in bacteria that have never been susceptible to that particular drug. Such natural insensitivity can be due to: o lack of affinity of the drug for the bacterial target o inaccessibility of the drug into the bacterial cell o extrusion of the drug by chromosomally encoded active exporters o innate production of enzymes that inactivate the drug  Mechanisms for drug resistance Resistance to antibiotics typically occurs by one or more of the following mechanisms: o prevention of drug penetration or accumulation o enzymatic modification (inactivation) of the drug o modification of the antibacterial target o enzymatic bypass  PREVENTION OF DRUG PENETRATION OR ACCUMULATION This strategy involves: in Gram negative pathogens: changes in outer membrane lipid composition, porin channel selectivity, and/or porin channel concentrations inhibiting drug uptake in Gram positive and negative pathogens: production of efflux pumps that actively transport the antimicrobial drug out of the cell and prevent the accumulation of drug to a level that would be antibacterial Carbapenem resistance among P. aeruginosa: decreased amount of OprD porin in the outer membrane. Resistance to β-lactams, tetracyclins and quinolones occurs through active efflux out of the cell.  ENZYMATIC MODIFICATION OF THE DRUG Resistance genes may code for enzymes that: o chemically modify an antibiotic, thereby inactivating it o destroy an antibiotic through hydrolysis β-lactam resistance: enzymatic hydrolysis of the β-lactam ring (β-lactamases)  TARGET MODIFICATION Bacteria can become resistant by changing the “shape” of an antibiotic's target. These mutations often change the shape of the target, lowering the affinity to antibiotics, but not impairing their native function. Genetic changes impacting the active site of penicillin-binding proteins (PBPs) can inhibit the binding of β-lactam drugs and provide resistance to multiple drugs within this class (S. pneumoniae, S. aureus)  Methicillin-resistant Staphylococcus aureus (MRSA) Methicillin MRSA expresses an alternate form of penicillin-binding protein PBP2, called PBP2a, with reduced binding affinity for methicillin and all β-lactam drugs, with the exception of the newer fifth-generation cephalosporins designed specifically to kill MRSA VRSA are S. aureus strains resistant to vancomycin that is considered one of the last lines of defense against MRSA.  ENZYMATIC BYPASS When an antibacterial drug functions as an antimetabolite microbial resistance may occur in two ways: o the bacterial cell may develop a bypass that circumvents the need for the functional target enzyme o the pathogen may overproduce the target enzyme such that there is a sufficient amount of antimicrobial-free enzyme to carry out the proper enzymatic reaction antibiotic  MULTIDRUG-RESISTANT MICROBES (MDRs) MDRs are colloquially known as “superbugs” and carry one or more resistance mechanisms, making them resistant to multiple antibacterials. Several of the superbugs have been dubbed the ESKAPE pathogens: THESE PATHOGENS ARE ABLE TO “ESCAPE” MANY CONVENTIONAL FORMS OF ANTIMICROBIAL THERAPY