The concern with respect to antimicrobial
resistance and the associated health threat has gained
increasing attention and there has been difficulty in gaining
traction globally. Given the lack of success by the two
pathways established to date which have focused on: 1)
"replication of infective agent" and, 2) "immune system
enhancement," the current researcher has conceptualized
and developed the new, or third, mode of action pathway
represented by "site attachment inhibition (or, negation
of cellular attachment by infective agents)." The current
author anticipates site attachment inhibition therapeutics
to include drug (medication) based therapies, stem cell
based treatment (including prenatal and earlier spanning
back to spermatogenesis and oogenesis) incorporating new
generation immunization methods, and waveform (E.g.
electromagnetic radiation) based treatment. With respect
to viruses, support for the likely success of the new mode
of action pathway: A) the known CCR5-Δ32 mutation
achieves resistance (immunity) against HIV through
negation of cellular attachment; B) other areas of medicine
use analogous receptor antagonism (E.g. beta blocker
therapy); C) advanced IT uses analogous site attachment
inhibition to remove viruses. With respect to bacteria,
support for the likely success of the new mode of action
pathway: A) advanced IT uses analogous site attachment
inhibition to remove IT infections; B) glycoproteins are
key proteins/receptors for attachment and, analogous to
glycoprotein IIb/IIIa medications which inhibit (negate)
platelet aggregation and thrombus formation, it seems
reasonable to pursue antagonism or blockade of other
glycoprotein receptors in order to prevent bacterial
attachment to human cells (note: this is also relevant to
viral infections); C) the human immune system perhaps
coats infective agents in an attempt to negate cellular
attachment, therefore this mode of action represented by
site attachment inhibition makes scientific sense.
This publication extends on the previous literature
by the current researcher (author) through presentation of
the Case Example namely that of Clostridium Difficile.
Case Example: Clostridium Difficile
The Case Example to be used in this publication
is Clostridium Difficile. In a previous publication, HIV
was used as a Case Example. In brief, with regards to
HIV, for treatment of established infection, glycoprotein
antagonism/inhibition (similar to above) may be a pathway
of interest. For new generation immunization, mutagenesis
(or, knockout) of genes related to CCR5, CXCR4 and
CD4 was discussed. That being said, attention must be
directed toward correctly identifying the target receptors
and appreciating the difference between association and
causation. Looking at mutations noticed in the human
population and connecting this to the innate resistance
they possess to certain infections is not enough as this
may simply represent association as opposed to causation.
Even the known CCR5-Δ32 mutation has not been
completely confirmed as direct/causative of the inhibition
of attachment to (and transfer / entry into) human cellular
biology by the given pathogen.
Clostridium Difficile attaches to (and, enters
by way of) human cellular epithelium lining the
gastrointestinal tract. Specifically, the relevant epithelium
contains surface proteins/receptors (in the gastrointestinal
tract, which clostridium difficile attaches to) including:
(1) peptidases (a form of protease); (2) esterases; (3)
glycoproteins. Depending on the text, peptidase can
be used synonymously with protease or alternatively
distinguished by way of the the polypeptides commonly
There are protease inhibitors with respect to Mode
of Action Pathway (1) replication of infective agent. With
respect to site attachment inhibition (Mode of Action
Pathway 3) protease inhibition (or, inhibition of peptidases)
would be the target and this would be by way of measures
including selective targeting of receptor mediated
endocytosis (RME; clathrin mediated endocytosis)
moderated by proteases in the plasma membrane of the
human cells (gastrointestinal tract and elsewhere). This
means that instead of 'replication of infective agent' being
inhibited it is site attachment inhibition (or, inhibition of
receptor mediated endocytosis). Note, however, there is
overlap between the two methodologies.
Glycoprotein inhibition has been discussed
previously. An example where selective inhibition of
glycoproteins has occurred previously is with respect to
glycoprotein IIb/IIIa medications which inhibit (negate)
platelet aggregation and thrombus formation.
Esterases will be discussed in subsequent publications.
With regards to new generation immunization, as
discussed in previous publications, relevant issues include
- Selective mutagenesis or knockout of genes (including
prenatal or earlier, spanning back to spermatogenesis
and oogenesis) that govern relevant attachment transfer
of the infective agent into the human cellular biology.
New generation immunisation programes, based on site
attachment inhibition, have been discussed in previous
publications by the current author. There has been an
increasing interest in prenatal genetic therapy. Adult
genetic therapy remains of interest but poses particular
- Analysis of innate genetic variations for guidance.
For instance: CCR5-Δ32 is associated with innate immunity
to HIV with the homozygous and, perhaps heterozygous
variation not having been linked to any serious adverse
health states; heterozygous sickle cell gene variation (AS)
protects against Malaria, although homozygous variation
in that regard causes sickle cell anaemia (disease state).
- Attention must be directed toward correctly identifying
the target receptors and appreciating the difference between
association and causation. Looking at mutations noticed
in the human population and connecting this to the innate
resistance they possess to certain infections is not enough
as this may simply represent association as opposed to
causation. Even the known CCR5-Δ32 mutation has not
been completely confirmed as direct/causative of the
inhibition of attachment observed in research analyses.
Note: Site attachment inhibition is also able to be termed
- Ethics committee and community consideration remains
important with biological and medical treatments, as
outlined in previous publications. Respect for biology should remain at the highest level as it involves; as with
other entities, potential life forms.
The use of site attachment inhibition to treat
cancer including by way of antagonism of transmembrane
glycoproteins called cell adhesion molecules, with
examples of these glycoproteins including selectins,
integrins, syndecans, and cadherins. Other areas relevant
to cancer have been detailed in previous publications.
USA has been assisting with HIV in Africa for
prehaps over fifty years, yet to date it has not had any widely accepted cases of curative success. This is the same
with other countries. USA reportedly has temporarily
delegated or transferred some of its program to countries
including Russia but it is not clear whether this includes
any of the assistance regarding Africa. Given the length
of the time period USA has had without major success
regarding Africa and HIV it may be that the goals set by
United Nations need to be lengthened. With that said, it
should remain important that Africans not be victims
blamed for the time period length being taken to assist
with their issues.
An important note is that the issues regarding
antimicrobial resistance and metaphorical superbugs span
widely and are not just focused on Africa or HIV.
In conclusion, this paper presents the new, or
third, mode of action pathway in antimicrobial therapy
represented by site attachment inhibition therapeutics.
Site attachment inhibition therapeutics consists of: 1.
Treatment of established infections (E.g. medication
based); 2. New generation immunization programs
(preventative treatment) utilizing stem cell based therapy.
New content presented in this manuscript revolves around
the Case Example of Clostridium Difficile. Future
publications are planned to discuss CRISPR, including
CRISPR-Cas9, and related technologies as solutions with
regards to association and causation issues.