Antibiotics/Antimicrobials
Benjamin U. Ebeshi B.Pharm PhD
Associate Professor
Department of Pharmaceutical & Medicinal Chemistry
Faculty of Pharmacy, Madonna University
Elele campus,
Nigeria
E. mail: ben.ebeshi@ndu.edu.ng
Antibiotic/Antimicrobial
Chemotherapy
Microbial Sources of Antibiotics
Mechanisms of Antimicrobial Action
Modes of Antimicrobial Action
Classification of Antibiotics
β-Lactam antibiotics
β-Lactam antibiotics are the most widely produced and used antibacterial drugs in the world, and have been ever since their initial clinical trials in 1941.
β-Lactams are divided into several classes based on their structure and function; and are often named by their origin, but all classes have a common β-Lactam ring structure.
Penicillins
Figure 20.6
Target- Cell Wall Synthesis
The bacterial cell wall is a cross linked polymer called peptidoglycan which allows a bacteria to maintain its shape despite the internal turgor pressure caused by osmotic pressure differences.
If the peptidoglycan fails to crosslink the cell wall will lose its strength which results in cell lysis.
The cross linking reaction is catalyzed by a class of transpeptidases known as penicillin binding proteins (PBP)
All β-lactams disrupt the synthesis of the bacterial cell wall by interfering with the transpeptidase which catalyzes the cross linking process.
Mechanism
Mechanism of β-Lactam Drugs
The hydroxyl attacks the amide and forms a tetrahedral intermediate.
Mechanism of β-Lactam Drugs
The tetrahedral intermediate collapses, the amide bond is broken, and the nitrogen is reduced.
Mechanism of β-Lactam Drugs
The PBP is now covalently bound by the drug and cannot perform the cross linking action.
Classes of β-Lactams
The classes of β-lactams are distinguished by the variation in the ring adjoining the β-lactam ring and the side chain R.
Penicillin
Penicillins- Natural
Natural penicillins are those which can be obtained directly from the penicillium mould and do not require further modification. Many species of bacteria are now resistant to these penicillins.
Penicillin G
not orally active
Penicillin G in Acidic Conditions
Penicillin G could not be administered orally due to the acidic conditions of the stomach.
Modification of β-Lactams
β-Lactam type antibiotics can be modified at various positions to improve their ability to:
-be administered orally (survive acidic conditions)
-be tolerated by the patient (allergies)
-penetrate the outer membrane of Gram (-) bacteria
-prevent hydrolysis by β-lactamases
-acylate the PBPs of resistant species (there are many different PBPs)
Penicillin V
Penicillin V is produced when phenoxyacetic acid rather than phenylacetic acid is introduced to the penicillium culture. Adding the oxygen decreases the nucleophilicity of the carbonyl group, making penicillin V acid stable and orally viable.
Penicillinase (β Lactamase)
Figure 20.8
Semi-Synthetic Penicillins
The acyl side chain of the penicillin molecule can be cleaved using enzyme or chemical methods to produce 6-APA, which can further be used to produce semi-synthetic penicillins or cephalosporins
75% of the penicillin produced is modified in this manner.
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Penicillinase-resistant Penicillins or Antistaphylococcal
Penicillins which have bulky side groups can block the β-Lactamases which hydrolyze the lactam ring.
Penicillins- Antistaphylococcal
These lactamases are prevalent in S. aureus and S. epidermidis, and render them resistant to Penicillin G and V. This necessitated the development of semi-synthetic penicillins through rational drug design.
Methicillin was the first penicillin developed with this type of modification, and since then all bacteria which are resistant to any type of penicillin are designated as methicillin resistant. (MRSA- methicillin-resistant S. aureus).
Methicillin is acid sensitive and has been improved upon by adding electron withdrawing groups, as was done in penicillin V, resulting in drugs such as cloxacillin and nafcillin.
Penicillins- Antistaphylococcal
Due to the bulky side group, all of the antistaphylococcal drugs have difficulty penetrating the cell membrane and are less effective than other penicillins.
Penicillins- Aminopenicillins
In order to increase the range of activity, the penicillin has been modified to have more hydrophilic groups, allowing the drug to penetrate into Gram (-) bacteria via the porins.
Ampicillin R=Ph
Amoxicillin R= Ph-OH
Penicillins- Aminopenicillins
These penicillins have a wider range of activity than natural or antistaphylococcal drugs, but without the bulky side groups are once again susceptible to attack by β-lactamases
The additional hydrophilic groups make penetration of the gut wall difficult, and can lead to infections of the intestinal tract by H. pylori
Penicillins- Aminopenicillins
Due to the effectiveness of the aminopenicillins, a second modification is made to the drug at the carboxyl group.
Changing the carboxyl group to an ester allows the drug to penetrate the gut wall where it is later hydrolyzed into the more polar active form by esterase enzymes.
This has greatly expanded the oral availability of the aminopenicillin class.
Penicillins- Extended Spectrum
Extended spectrum penicillins are similar to the aminopenicillins in structure but have either a carboxyl group or urea group instead of the amine
Penicillins- Extended Spectrum
Like the aminopenicillins the extended spectrum drugs have an increased activity against Gram (-) bacteria by way of the import porins.
These drugs also have difficulty penetrating the gut wall and must be administered intravenously if not available as a prodrug.
These are more effective than the aminopenicillins and not as susceptible to β-lactamases.
Examples include piperacillin and ticarcillin
Cephalosporins
Cephalosporins were discovered shortly after penicillins entered into widespread product, but not developed till the 1960’s.
Cephalosporins are similar to penicillins but have a 6 member dihydrothiazine ring instead of a 5 member thiazolidine ring.
7-aminocephalosporanic acid (7-ACA) can be obtained from bacteria, but it is easier to expand the ring system of 7-ACA because it is so widely produced.
Other Inhibitors of Cell Wall Synthesis
Figure 20.9
Cephalosporins
Unlike penicillin, cephalosporins have two side chains which can be easily modified. Cephalosporins are also more difficult for β-lactamases to hydrolyze.
Mechanism of Cephalosporins
The acetoxy group (or other R group) will leave when the drug acylates the PBP.
Cephalosporins- Classification
Cephalosporins are classified into four generations based on their activity.
Later generations generally become more effective against Gram (-) bacteria due to an increasing number of polar groups (also become zwitterions.)
Ceftazidime (3rd gen) in particular can cross blood brain barrier and is used to treat meningitis.
Later generations are often the broadest spectrum and are reserved against penicillin resistant infections to prevent the spread of cephalosporin resistant bacteria.
Carbapenems
Carbapenems are a potent class of β-lactams which attack a wide range of PBPs, have low toxicity, and are much more resistant to β-lactamases than the penicillins or cephalosporins.
Thienamycin
Carbapenems
Thienamycin, discovered by Merck in the late 1970’s, is one of the most broad spectrum antibiotics ever discovered.
It uses import porins unavailable to other β-lactams to enter Gram (-) bacteria.
Due to its highly unstable nature of this drug and its derivatives are created through synthesis, not bacterial fermentation.
Monobactams
The only clinically useful monobactam is aztreonam. While it resembles the other β-lactam antibiotics and targets the PBP of bacteria, its mechanism of action is significantly different.
It is highly effective in treating Gram (-) bacteria and is resistant to many β-lactamases
β-Lactamase Inhibitors
There are currently three clinically available β-lactamase inhibitors which are combined with β-lactams; all are produced through fermentation.
These molecules bind irreversibly to β-lactamases but do not have good activity against PBPs. The rings are modified to break open after acylating the enzyme.
Clavulanic acid
Sulbactam
β-Lactam/Inhibitor combinations
Aminopenicillins:
ampicillin-sulbactam = Unasyn®
amoxicillin-clavulante = Augmentin®
Extended-Spectrum Penicillins
piperacillin-tazobactam = Zosyn®
ticarcillin-clavulanate = Timentin®
Other Inhibitors of Cell Wall Synthesis
with molecular formula C66H103N17O16S
Other Inhibitors of Cell Wall Synthesis
Inhibitors of Protein Synthesis
Inhibitors of Protein Synthesis
Inhibitors of Protein Synthesis
Name of Compound | R1 | R2 | R3 | R4 | R5 |
Tetracycline | H | OH | CH3 | H | H |
Oxytetracycline | OH | OH | CH3 | H | H |
Chlortetracycline | H | OH | CH3 | Cl | H |
Doxycycline | OH | H | CH3 | H | H |
Rolitetracycline | H | OH | CH3 | H | |
Inhibitors of Protein Synthesis
Polymyxin B (Gram negatives)
Injury to the Plasma Membrane
Inhibitors of Nucleic Acid Synthesis
Competitive Inhibitors
Figure 5.7
Antifungal Drugs
Antifungal Drugs
A. Natural antifungal agents
Antifungal Drugs
B. Synthetic antifungals
They are used in the treatment of dermatophytoses and non-systemic candidiasis
E.g., Clotimazole, flucytosine, miconazole, ketoconazole, econazole and fluconazole.
B.U. Ebeshi B. Pharm PhD
9/30/2021