BETA LACTAMS

BY GROUP 1….
INTRODUCTION
 β-lactam antibiotics (beta-lactam antibiotics) are
antibiotics that contain a beta-lactam ring in their
chemical structure. This includes penicillin
derivatives (penams), cephalosporins and
cephamycins (cephems), monobactams,
carbapenems[1] and carbacephems.
BETA LACTAM ANTIBIOTIC
 Most β-lactam antibiotics work by inhibiting cell
wall biosynthesis in the bacterial organism and
are the most widely used group of antibiotics.
Until 2003, when measured by sales, more than
half of all commercially available antibiotics in
use were β-lactam compounds.[3 The first β-
lactam antibiotic discovered, penicillin, was
isolated from a strain of Penicillium rubens
(named as Penicillium notatum at the time).
NOMENCLATURE

 BETA-lactams are classified according to their core ring

structures.

 β-lactams fused to saturated five-membered rings:

 β-lactams containing thiazolidine rings are named
penams.
 β-lactams containing pyrrolidine rings are named
carbapenams.
 β-lactams fused to oxazolidine rings are named
oxapenams or clavams.
 β-lactams fused to unsaturated five-membered
rings:
 β-lactams
containing 2,3-dihydrothiazole rings are
named penems.
 β-lactams
containing 2,3-dihydro-1H-pyrrole rings
are named carbapenems.
 β-lactams fused to unsaturated six-membered rings:
 β-lactams containing 3,6-dihydro-2H-1,3-thiazine rings are
named cephems.
 β-lactams containing 1,2,3,4-tetrahydropyridine rings are
named carbacephems.
 β-lactams containing 3,6-dihydro-2H-1,3-oxazine rings are
named oxacephems.
 β-lactams not fused to any other ring are named
monobactams.
MEDICAL USE

 β-lactam antibiotics are indicated for the

prevention and treatment of bacterial infections
caused by susceptible organisms. At first, β-
lactam antibiotics were mainly active only against
Gram-positive bacteria, yet the recent
development of broad-spectrum β-lactam
antibiotics active against various Gram-negative
organisms has increased their usefulness.
SIGNIFICANCE OF BETA LACTAMS

 β-Lactams represent one of the most important

groups of antibiotics prescribed for antibacterial
treatment today. They stop bacterial growth by
inhibiting PBPs that are indispensable for the
cross-linking process during cell wall biosynthesis.
SOME CLASSES OF BETA LACTAM DRUGS

 Penicillins. These antibiotics (most of which end in the

suffix -cillin) contain a nucleus of 6-animopenicillanic acid
(lactam plus thiazolidine) ring and other ringside chains.
The group includes natural penicillins, beta-lactamase-
resistant agents, aminopenicillins, carboxypenicillins, and
ureidopenicillins.
 Cephalosporins. They contain a 7-aminocephalosporanic
acid nucleus and side-chain containing 3,6-dihydro-2 H-
1,3- thiazane rings. Cephalosporins are traditionally
divided into five classes or generations, although
acceptance of this terminology is not universal.
 Carbapenems. Their defining structure is a carbapenem
coupled to a beta-lactam ring that confers protection
against most beta-lactamases, although resistance to
these compounds is a significant issue and occurs mainly
among gram-negative pathogens (e.g., Klebsiella
pneumoniae, Pseudomonas aeruginosa, and Acinetobacter
baumannii), which produce different classes of beta-
lactamases termed as carbapenemase.
 Monobactams. The beta-lactam ring stands alone and not
fused to another ring.
PENICILLIN

 Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics

originally obtained from Penicillium moulds, principally P.
chrysogenum and P. rubens. Most penicillins in clinical use are
synthesised by P. chrysogenum using deep tank fermentation and then
purified.A number of natural penicillins have been discovered, but
only two purified compounds are in clinical use: penicillin G
(intramuscular or intravenous use) and penicillin V (given by mouth).
Penicillins were among the first medications to be effective against
many bacterial infections caused by staphylococci and streptococci.
They are still widely used today for different bacterial infections,
though many types of bacteria have developed resistance following
extensive use.
TYPES OF PENICILLIN

 Natural penicillins
 Penicillin G (benzylpenicillin) was first produced from a penicillium fungus
that occurs in nature. The strain of fungus used today for the manufacture of
penicillin G was created by genetic engineering to improve the yield in the
manufacturing process. None of the other natural penicillins (F, K, N, X, O, U1
or U6) are currently in clinical use.

 Semi-synthetic penicillin

 Penicillin V (phenoxymethylpenicillin) is produced by adding the precursor

phenoxyacetic acid to the medium in which a genetically modified
strain[dubious – discuss] of the penicillium fungus is being cultured.
STRUCTURE OF PENICILLIN

 The key structural feature of the penicillins is the four-

membered β-lactam ring; this structural moiety is
essential for penicillin's antibacterial activity. The β-
lactam ring is itself fused to a five-membered thiazolidine
ring. The fusion of these two rings causes the β-lactam
ring to be more reactive than monocyclic β-lactams
because the two fused rings distort the β-lactam amide
bond and therefore remove the resonance stabilisation
normally found in these chemical bonds. An acyl side side
chain attached to the β-lactam ring
MEDICAL USAGE OF PENICILLIN

 Penicillin G is licensed for use to treat septicaemia,

empyema, pneumonia, pericarditis, endocarditis and
meningitis caused by susceptible strains of staphylococci
and streptococci. PENICILLIN V is used for the same
bacterial infections as those of penicillin G and is the most
widely used form of penicillin. However, it is not used for
diseases, such as endocarditis, where high blood levels of
penicillin are required.
CEPHALOSPORINS

 Thecephalosporins are a class of β-lactam

antibiotics originally derived from the fungus
Acremonium, which was previously known as
Cephalosporium.

 Togetherwith cephamycins, they constitute a

subgroup of β-lactam antibiotics called cephems.
CEPHALOSPORIN - STRUCTURE
CEPHALOSPORIN STRUCTURE

 Cephalosporin contains a 6-membered dihydrothiazine

ring. Substitutions at position 3 generally affect
pharmacology; substitutions at position 7 affect
antibacterial activity, but these cases are not always true.
MEDICAL USAGE OF CEPHALOSPORINS

 Cephalosporins can be indicated for the prophylaxis and

treatment of infections caused by bacteria susceptible to
this particular form of antibiotic. First-generation
cephalosporins are active predominantly against Gram-
positive bacteria, such as Staphylococcus and
Streptococcus.
CARBAPENEMS
 Carbapenems are a class of very effective antibiotic
agents most commonly used for the treatment of severe
bacterial infections. This class of antibiotics is usually
reserved for known or suspected multidrug-resistant (MDR)
bacterial infections. Similar to penicillins and
cephalosporins, carbapenems are members of the beta-
lactam antibiotics drug class, which kill bacteria by
binding to penicillin-binding proteins, thus inhibiting
bacterial cell wall synthesis.
MEDICAL USAGE OF CARBAPENEMS

 Intra-abdominal infections
 The carbapenem ertapenem is one of several first-line agents recommended by the
Infectious Disease Society of America for the empiric treatment of community-
acquired intra-abdominal infections of mild-to-moderate severity. Agents with anti-
pseudomonal activity, including doripenem, imipenem, and meropenem, are not
recommended in this population. Doripenem, imipenem, and meropenem are
recommended for high-risk community-acquired abdominal infections and for
abdominal infections that are hospital-acquired.

 Complicated urinary tract infections

 A 2015 systematic review found little evidence that would support the identification
of a best antimicrobial regimen for complicated urinary tract infections, but
identified three high-quality trials supporting high cure rates with doripenem,
including in patients with levofloxacin-resistant E. coli infections.
ADVERSE EFFECTS OF CARBAPENEMS

 Serious and occasionally fatal allergic reactions can occur

in people treated with carbapenems. Seizures are a dose-
limiting toxicity for both imipenem and meropenem.
MONOBACTAMS

 Monobactams are monocyclic and bacterially-produced β-lactam antibiotics.

The β-lactam ring is not fused to another ring, in contrast to most other β-
lactams. Monobactams are effective only against aerobic Gram-negative
bacteria (e.g., Neisseria, Pseudomonas). Siderophore-conjugated
monobactams show promise for the treatment of multi drug-resistant
pathogens.

 Aztreonam is a commercially available monobactam antibiotic. Other

examples of monobactams are tigemonam, nocardicin A, and tabtoxin.
ADVERSE EFFECTS AND MECHANISM OF
MONOBACTAMS
 Adverse effects to monobactams can include skin rash and
occasional abnormal liver functions.[citation needed]

 Monobactam antibiotics exhibit no IgE cross-reactivity

reactions with penicillin but have shown some cross
reactivity with cephalosporins, most notably ceftazidime,
which contains an identical side chain as aztreonam.[4]
Monobactams can trigger seizures in patients with history
of seizures, although the risk is lower than with penicillins
MECHANISM OF ACTION OF BETA
LACTAMS
 β-lactam antibiotics are bactericidal, and act by inhibiting
the synthesis of the peptidoglycan layer of bacterial cell
walls. The peptidoglycan layer is important for cell wall
structural integrity,especially in Gram-positive organisms,
being the outermost and primary component of the wall.
The final transpeptidation step in the synthesis of the
peptidoglycan is facilitated by DD-transpeptidases, also
known as penicillin binding proteins (PBPs). PBPs vary in
their affinity for penicillin and other β-lactam antibiotics.
The number of PBPs varies between bacterial species
 β-lactam antibiotics are analogues of d-alanyl-d-alanine—
the terminal amino acid residues on the precursor
NAM/NAG-peptide subunits of the nascent peptidoglycan
layer. The structural similarity between β-lactam
antibiotics and d-alanyl-d-alanine facilitates their binding
to the active site of PBPs. The β-lactam nucleus of the
molecule irreversibly binds to (acylates) the Ser403
residue of the PBP active site. This irreversible inhibition
of the PBPs prevents the final crosslinking
(transpeptidation) of the nascent peptidoglycan layer,
disrupting cell wall synthesis.
 GUANINE OXIDATION :Another possibility that has been
proposed to account for much of the cytotoxicity of beta
lactams focuses on the oxidation of the guanine
nucleotide in the bacterial nucleotide pool.[15] The
incorporation of oxidized guanine nucleotide into DNA
could cause cytotoxicity. Bacterial cytotoxicity could arise
from incomplete repair of closely spaced 8-oxo-2'-
deoxyguanosine lesions in the DNA resulting in double-
strand breaks.
POTENCY OF BETA LACTAMS

 Two structural features of β-lactam antibiotics have been correlated with

their antibiotic potency.The first is known as "Woodward's parameter", h, and
is the height (in angstroms) of the pyramid formed by the nitrogen atom of
the β-lactam as the apex and the three adjacent carbon atoms as the base.
The second is called "Cohen's parameter", c, and is the distance between the
carbon atom of the carboxylate and the oxygen atom of the β-lactam
carbonyl.This distance is thought to correspond to the distance between the
carboxylate-binding site and the oxyanion hole of the PBP enzyme. The best
antibiotics are those with higher h values (more reactive to hydrolysis) and
lower c values (better binding to PBPs).
Beta lactam applications in aquaculture

 β-Lactams
 Amoxicillin - Piscirickettsia salmonis -blaTEM
 β-Lactams - Korean fish farm effluents - blaTEM, blaCTX, blaSHV
 Aminoglycosides -Piscirickettsia salmonis -sat1 and aadA1
 β-lactams are antibiotics with a wide range of therapeutic
activities and minimal side effects. This class of antibiotics
interfere with peptidoglycan synthesis, which is a major
component of bacterial cell walls88 and destroys the
integrity of the cell walls, causing lysis of the cell. Common
β-lactam antibiotics used in aquaculture include amoxicillin,
cephalosporins, penicillin, ampicillin, cephalexin, cefradine
and cefotaxime. The following are some recent reports on
the use of β-lactams in the aquaculture industry: Brazil,
Italy, Turkey, Chile, China, Vietnam, Korea, and South
Africa.
BACTERIA RESISTANCE TO BETA LACTAMS

 Antibiotictarget replacement mechanisms are

common in β-lactam resistance in Streptococcus
pneumoniae, glycopeptide resistance in
Enterococci, methicillin resistance in S. aureus. In
Streptococcus β-lactam, resistance is developed
by production of mosaic PBP, which binds through
transformation
HOW DO BACTERIA BECOME RESISTANT
TO BETA LACTAMS
 Resistance to β-lactam antibiotics predominantly
occurs through one of two mechanisms: 1) the
production of β-lactamases, which is the most
common resistance mechanism in Gram-negative
bacteria, or 2) the production of an altered PBP
with a lower affinity for most β-lactam antibiotics
THREE MECHANISMS

 The 3 mechanisms of β-lactam resistance are

reduced access to the PBPs, reduced PBP binding
affinity, and destruction of the antibiotic through
the expression of β-lactamase (enzymes that bind
and hydrolyze β-lactams)
BACTERIAL RESISTANCE TO BETA
LACTAMS – BETA LACTAMASE RESISTANCE
 Beta-Lactamase Resistance
 The most important mechanism of bacterial resistance to beta-lactam antimicrobials is
enzymatic inactivation by beta-lactamases via cleavage of the 4-member beta-lactam ring.
Cleavage results in the inability of the drugs to bind to their target PBPs. More than 800
unique beta-lactamases are known, representing six major classes, with the enzyme varying
with the organism and drugs targeted varying with the enzyme. The increase in the number of
enzymes reflects, in part, pressure brought with the increasingly widespread use of beta-
lactam antimicrobials and the continued manipulation of the drugs in an attempt to
circumvent bacterial beta-lactamase production. For example, the addition of larger R groups
on the beta-lactam structure rendered cephalosporins resistant to penicillinases.

 However, cephalosporinases emerged with continued use of first-generation cephalosporins.

Second- and third-generation cephalosporins reflect modifications, including larger R groups
that hindered beta-lactamase access to the beta-lactam ring. Inhibitors of beta-lactamases
(eg, clavulanic acid and sulbactam) were added to minimize penicillin destruction.
Subsequently, newer beta-lactamases have emerged.
SPECIFIC BACTERIAL BINDING PROTEINS

 Specific Bacterial-binding Proteins

 Resistance to beta-lactam antimicrobial agents can be acquired via
alterations in the PBP targets of these drugs. A loss or decrease in
affinity of crucial PBP can lead to a sizable increase in resistance to
beta-lactam antimicrobials. For example, resistance of enterococci to
cephalosporins appears to reflect the lack of affinity of a PBP to this
subclass of drugs. Changes in PBP-2 of Staphylococcus spp render the
organism resistant to all beta-lactam antimicrobials. Methicillin
resistance in Staphylococcus spp reflects acquisition of the mec gene,
which results in a mutation in PBP-2. As such, no beta-lactam can
bind to this protein, resulting in resistance to all beta-lactam drugs,
including carbapenems and most generations of cephalosporins.
Problematically, genes conferring methicillin resistance may be
accompanied by genes conferring multidrug resistance.
CELL WALL DEFICIENT MICROBES

 Organisms that have no cell wall, such as Mycoplasma, are

intrinsically resistant to beta-lactam antimicrobials. A
phenotypic form of resistance can occur when
spheroplasts (incomplete cell wall) or protoplasts
(absence of cell wall) are present. These so-called L-forms
must be present in a hyperosmotic environment (eg, the
renal medulla) to survive; otherwise, they will lyse. The
clinical relevance of this form of resistance is unclear.
BETA LACTAM IN AQUA

 Withthe advancement of the aquaculture

industry, the incidence of diseases has increased
due to the high-density intensive aquaculture
mode. Additionally, the overuse of drugs by
aquaculturists, the clinical effects of human or
animal drugs on aquaculture products should not
be ignored. According to the EU Commission
Regulation 37/2010, penicillins are β-LA licensed
for aquaculture.
BETA LACTAMASE

 Beta-lactam antibiotics, named after their

beta-lactam ring in their chemical
structure, are a type of antibiotic that kills
bacteria. Beta-lactamase is an enzyme that
these bacteria produce to disable beta-
lactam antibiotics.
BETA LACTAMASE INHIBITIRS

 Clavulanic acid, sulbactam, and tazobactam are beta-

lactamase inhibitors. Whereas clavulanic acid is used in
combination with amoxicillin and ticarcillin, sulbactam
sodium is used in combination with ampicillin and
cefoperazone, and tazobactam in combination with
piperacillin
BACTERIA PRODUCING BETA LACTAMASE

 Extended-spectrum beta-lactamases (ESBL) are

enzymes produced by gram-negative bacteria such
as Klebsiella pneumoniae and Escherichia coli as
well as by species from other genera, such as
Enterobacter sp., Salmonella sp., Proteus sp.,
Serratia marcescens, Shigella dysenteriae,
Pseudomonas aeruginosa,
ANTIBIOTIC DRUGS EFFECTIVE AGAINST
BETA LACTAMS
 Thesecond-generation cephalosporins include
cefaclor (Ceclor), cefprozil (Cefzil) and
cefuroxime axetil (Ceftin). Compared with first-
generation cephalosporins, these drugs have
improved activity